Analysis of p.His199Tyr variant, CFTR gene, CF Transmembrane conductance Regulator protein (1480 residues)
Data provided and calculated by CYSMA must be considered as predictions.
They are meant for educational purposes only and are provided with NO WARRANTY with respect to their biological reliability.
The alignment does not show any divergent sequences.
The mutant residue cannot be found in the alignment.
There is no gap in the alignment.
The wild-type residue H199 is conserved at 100% among the CFTR orthologs
*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 199). AAPIR appears in green if it is more than 10% compared to AAPI, in red if less than 10%. Click here for more details on the alignment.
Divergencies show the amino acids which have been selected in the evolution.
If you find your variant among them with a high occurrence, there are good chances that your variant will most likely either have a small impact or no impact at all on the CFTR function.
Please note that CYSMA does not consider splicing alterations.
Refer to the Help page for more details.
Informativity of this alignment: P0 = 0.0438, with an average substitution per position of 3.13.
This means that you have a probability of 0.9562 (95.62%) that position 199 is invariant because it is functionally constrained.
Refer to the Help page for more details.
CYSMA's visualizing modules for Ortholog conservation:
⬇ Download the region alignment (50 residues, Fasta format)
⬇ Download the CFTR phylogenic tree
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Homo sapiens
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Pan troglodytes
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Pongo pygmaeus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Gorilla gorilla
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Nomascus leucogenys
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Macaca mulatta
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Macaca nemestrina
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Macaca fascicularis
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Papio anubis
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Callithrix jacchus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Chlorocebus aethiops
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Colobus guereza
I
S
I
G
Q
L
V
S
F
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Ateles geoffroyi
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Plecturocebus moloch
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
V
F
Saimiri boliviensis
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Aotus nancymaae
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
I
W
E
L
L
Q
A
S
A
F
Otolemur garnettii
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Microcebus murinus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
M
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Vicugna pacos
I
S
I
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
S
T
F
Sus scrofa
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Bos taurus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
F
T
F
Muntiacus reevesi
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
F
T
F
Muntiacus muntjak
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
F
T
F
Ovis aries
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
A
F
T
F
Equus caballus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Canis familiaris
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Loxodonta africana
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
I
W
D
L
L
Q
A
S
A
F
Mustela furo
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Oryctolagus cuniculus
I
S
I
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
S
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Atelerix albiventris
I
S
I
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Dasypus novemcinctus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Rhinolophus ferrumequinum
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
M
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Cavia porcellus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Monodelphis domestica
I
S
T
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
V
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Ornithorhynchus anatinus
I
S
T
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
M
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Didelphis virginiana
I
S
T
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
V
P
L
Q
V
V
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Trichosurus vulpecula
I
S
T
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
V
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Carollia perspicillata
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
E
L
L
Q
A
S
A
F
Mus musculus
I
S
I
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
I
W
I
A
P
L
Q
V
T
L
L
M
G
L
L
W
D
L
L
Q
F
S
A
F
Rattus norvegicus
I
S
I
G
Q
L
I
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
I
W
I
A
P
L
Q
V
V
L
L
M
G
L
L
W
D
L
L
Q
F
S
A
F
Gallus gallus
I
S
T
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
L
W
D
M
L
Q
A
S
A
F
Taeniopygia guttata
I
S
T
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
A
L
L
M
G
L
L
W
D
M
L
E
A
S
A
F
Xenopus tropicalis
I
S
T
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
L
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Xenopus laevis
I
S
T
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
L
A
L
A
H
F
V
W
I
A
P
L
Q
V
L
L
L
M
G
L
L
W
D
L
L
Q
A
S
A
F
Squalus acanthias
I
D
T
G
Q
L
V
S
L
L
S
N
N
L
N
K
F
D
E
G
V
A
V
A
H
F
V
W
I
A
P
V
Q
V
V
L
L
M
G
L
I
W
N
E
L
T
E
F
V
F
Danio rerio
I
S
T
G
Q
L
V
S
L
M
S
A
N
L
G
K
F
D
Q
S
L
G
M
A
H
F
I
W
I
S
P
L
Q
C
I
L
C
T
G
L
I
W
E
L
I
D
V
N
S
F
Oryzias latipes
I
T
T
G
Q
L
V
S
L
M
S
A
H
L
N
K
L
D
E
S
L
G
L
A
H
F
V
W
I
T
P
L
Q
C
M
L
C
A
G
L
V
W
E
L
I
E
V
N
S
L
Takifugu rubripes
I
S
T
D
Q
L
V
S
L
M
S
A
H
L
N
K
L
D
E
S
L
G
L
A
H
F
I
W
I
T
P
L
Q
C
I
L
C
V
G
L
I
W
E
L
I
E
V
N
G
F
Tetraodon nigroviridis
I
S
T
D
Q
L
V
S
L
M
S
A
H
L
N
K
L
D
E
S
L
G
L
A
H
F
I
W
I
T
P
L
Q
C
I
L
C
V
G
L
I
W
E
L
I
E
V
N
G
F
Caenorhabditis elegans
T
N
S
G
Q
I
I
Q
L
L
N
T
D
A
A
K
L
E
Q
A
F
L
F
A
H
Y
V
W
L
C
P
L
L
M
F
F
Y
A
Y
I
L
W
S
M
F
G
F
C
C
L
Species color legend (basic classification):
Great apes | Other monkeys | Prosimians | Other mammals | Lizards | Birds | Amphibians | Fishes | Insects | Nematods | Tunicates | Echinoderms
Ortholog sequences have been selected from the Ensembl(1) and
NCBI websites. Alignment has been performed with
ClustalW(2), version 1.83 or 2.0.7.
Trees have been built using Phylogeny.fr(3), based on the alignments.
Software used is PhyML 3.0 aLRT with default parameters. Pictures of trees have been made using Phylip at Mobyle.
AAPI and AAPIR have been calculated thanks to Bioperl.
Domain conservation:
The domain MSD1 of CF Transmembrane conductance Regulator has been shown to interact with:
The residue p.His199 (MSD1) seems to play a key role in the CFTR function:
p.His199 is involved in the pore construction.
The residue p.His199 belongs to the domain MSD1.
69
422
is the membrane-spanning domain 1, composed of six transmembrane helices (TM1-TM6). Four of the six TMs protrude into the cytosol to form the intracellular loops ICL1 (between TM2 and TM3) and ICL2 (between TM4 and TM5). ICL1 contacts NBD1 at the level of the ATP-binding site, while ICL2 binds in a groove located at the surface of NBD2.
MSD1: is the membrane-spanning domain 1, composed of six transmembrane helices (TM1-TM6). Four of the six TMs protrude into the cytosol to form the intracellular loops ICL1 (between TM2 and TM3) and ICL2 (between TM4 and TM5). ICL1 contacts NBD1 at the level of the ATP-binding site, while ICL2 binds in a groove located at the surface of NBD2.
MSD1 of CF Transmembrane conductance Regulator domain alignment including p.His199 residue.
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated). !AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 199). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
Divergencies
Residues present in more than 10% of the sequences are highlighted in blue.
A - 6.76%
F - 4.20%
G - 1.63%
I - 14.22%
L - 20.28%
M - 5.59%
N - 4.43%
P - 3.03%
Q - 0.47%
S - 1.17%
T - 1.17%
V - 17.02%
W - 0.23%
Y - 1.86%
The wild-type residue H199 belongs to the MSD1 domain and is conserved at 17.95% among the MSD1 homologs (77 / 429 MSD1 homologs)
The variant H199Y has been found among the MSD1 homologs with a non significant frequency: 1.86% (8 / 429 MSD1 homologs)
Divergencies show the amino acids which have been selected in the evolution. Residues present in more than 10% of the sequences are highlighted in blue.
Please note that CYSMA does not consider splicing alterations.
Refer to the Help page for more details.
CYSMA's visualizing modules for MSD1 domain conservation:
Sequence alignments for NBDs have all been extracted from Prosite(4). Sequence alignments for MSDs have been extracted using the PSI-BLAST web server.
Sequences alignments have been manually re-aligned using a structural alignment including the human CFTR and bacterian ABC transporters with know 3D structures (for MSDs and NBDs domains).
Predictions of secondary structures have been made with PsiPred(9)
, version 2.5, using Protein Multiple Sequences Alignments as input, in order to increase the accuracy of the prediction.
Amino acid frequencies have been calculated from a non redondant set defined by the RCSB.
The Help page will tell you more about it.
3D analysis:
Models provided and analysed by CYSMA must be considered as predictions, therefore be careful when interpreting the results. All efforts have been made to build structures of quality, however, they are provided with NO WARRANTY as to their accuracy with the real biological molecules studied.
Wild type and predicted mutant structures have been compared. You will find the results below.
Click on the MolProbity logo for complete details on the structure quality
This model is made of 37 α helices and of 20 β strands (and is mainly composed of helices (739 residues in helices against 102 in strands, for a total of 1480 amino acids)).
3D structures predicts H199 to be located in an α helice (which confirms PsiPred prediction) and Y199 in an α helice. Moreover, the residue is located in the core of this α helice (which contains 39 residues). Helix interior propensities of wild-type and mutant residues are 0.84 and 0.99. A potential Side chain interaction of the type i,i-4 has been detected between mutant residue and LEU195. This
interaction presents an attracting energy of -0.65 kcal/mol.
WARNING! The experimental 3D structure used for our predictions is the complete human CFTR structure which have been solved at a 3.7 Å resolution using cryo-electron microscopy (PDB: 5UAK; Liu et al. 2017). The overall resolution is fairly low so the CYSMA's 3D Automatic Annotation pipeline might have missed some important structural effects.
Solvent accessibility: the wild-type H199 and the mutant H199Y are predicted to be buried
The two residues have different charge properties, which could interfere with ionic bonds or potential inter- or intra-molecular interactions
With the mutant residue, the number of hydrogen bonds is reduced
H199
Y199
distance: 3.85 Å / angle: 1.71 rad between HIS 199 ND1 and TRP 202 NE1
distance: 3.48 Å / angle: 1.83 rad between HIS 199 NE2 and TRP 202 NE1
distance: 4.03 Å / angle: 2.25 rad between HIS 199 ND1 and GLY 85 O
distance: 3.86 Å / angle: 1.78 rad between TYR 199 OH and ILE 86 N
distance: 3.47 Å / angle: 2.08 rad between TYR 199 OH and MET 82 SD
The mutant residue is predicted to form comparable hydrophobic interactions than the wild-type The wild-type residue HIS is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is maintained in the mutant residue TYR
H199
Y199
4.73 Å between HIS 199 CG and PHE 81 CE2
4.44 Å between HIS 199 CB and PHE 81 CZ
4.46 Å between HIS 199 CD2 and PHE 81 CD2
4.46 Å between HIS 199 CE1 and ILE 203 CG1
4.99 Å between HIS 199 CG and TRP 202 CD1
4.91 Å between HIS 199 CD2 and TRP 202 CD1
4.54 Å between HIS 199 CE1 and TRP 202 CD1
4.46 Å between HIS 199 CG and LEU 88 CD1
4.45 Å between HIS 199 CB and LEU 88 CD1
5.00 Å between HIS 199 CE1 and LEU 88 CB
4.70 Å between HIS 199 CB and LEU 145 CD1
4.82 Å between TYR 199 CB and PHE 81 CE2
4.58 Å between TYR 199 CG and PHE 81 CE2
3.94 Å between TYR 199 CD2 and PHE 81 CD2
3.94 Å between TYR 199 CE2 and PHE 81 CD2
4.20 Å between TYR 199 CD1 and ILE 203 CG1
4.47 Å between TYR 199 CE1 and ILE 203 CG1
4.74 Å between TYR 199 CD1 and TRP 202 CD1
4.92 Å between TYR 199 CE1 and TRP 202 CD2
4.84 Å between TYR 199 CE2 and TRP 202 CD1
4.49 Å between TYR 199 CZ and TRP 202 CD1
4.37 Å between TYR 199 CB and LEU 88 CD1
4.52 Å between TYR 199 CG and LEU 88 CD1
4.81 Å between TYR 199 CD1 and LEU 88 CB
4.96 Å between TYR 199 CE1 and LEU 88 CD1
4.77 Å between TYR 199 CE2 and MET 82 CE
4.48 Å between TYR 199 CB and LEU 145 CD1
4.98 Å between TYR 199 CG and LEU 145 CD1
4.85 Å between TYR 199 CD2 and LEU 145 CD2
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
The mutant residue is not predicted to introduce steric clashes
H199
Y199
none
none
CYSMA's 3D visualizing module:
If you want to investigate further the structures, you can use
the JSmol applets of the wild-type (left) and mutant (right) structures.
Click on the JSmol applets' link to hide it.
You have a full access to Jmol commands with a simple right click on one applet.
JSmol Legends:
The residue at the position 199 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å).
Van der Waals contacts with the residue 199 are represented by dotted lines.
Amino acids involved in H-bonds with the residue 199 are labelled in blue.
Amino acids involved in steric clashes with the residue 199 are labelled in red.
The overall structure of the complete human CFTR is represented in ribbon diagrams (click on the Reset button to visualize the overall CFTR structure). The membrane-spanning domain MSD1 is represented in blue and MSD2 in light blue.The nucleotide-binding domain NBD1 is represented in orange, NBD2 in light salmon.The lasso domain is shown in red and the R domain in green.
The 3D structures used in CYSMA are models based on the CFTR experimental 3D structure in the channel-closed conformation (PDB: 5UAK; resolution: 3.9 Å). In the wild-type model, the (missing) loops and the (missing) R domain were built de novo using the software Modeller. For the variant models, the point mutation (homology modelling) are made on the fly with Modeller (more).
Each structure has been assessed with MolProbity(19).
Msms(20) is used to calculate solvent accessibility, and STRIDE(21) (plus stride2pdb)
for secondary structure assignment.
Secondary structure analyses in 3D models uses side chain interaction energies reviewed in (23), as well as amino-acids propensities for N-caps, N1-N3, helix middle, C3-C1 and C-caps extracted from (24)(PDB values).
Structural properties are calculated using an in-house developped program based for the USMA's 3D Automatic Annotation pipeline.
Click on the LOVD picture to check if a variant is described at position 199
Graphical display of the region at NCBI (including SNPs)
CYSMA Report:
Report for p.His199Tyr variant
CFTR orthologs conservation
The wild-type residue H199 is conserved at 100% among the CFTR orthologs
MSD1 homologs conservation
The wild-type residue H199 belongs to the MSD1 domain and is conserved at 17.95% among the MSD1 homologs (77 / 429 MSD1 homologs)
The variant H199Y has been found among the MSD1 homologs with a non significant frequency: 1.86% (8 / 429 MSD1 homologs)
Structural effects
The wild-type residue H199 seems to play a key role in the CFTR function. H199 is involved in the pore construction
Solvent accessibility: the wild-type H199 and the mutant H199Y are predicted to be buried
The two residues have different charge properties, which could interfere with ionic bonds or potential inter- or intra-molecular interactions
With the mutant residue, the number of hydrogen bonds is reduced
The mutant residue is predicted to form comparable hydrophobic interactions than the wild-type The wild-type residue HIS is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is maintained in the mutant residue TYR
The mutant residue is not predicted to introduce steric clashes