Is MYO7A p.Tyr403Cys (c.1208A>G) pathogenic?

MYO7A p.Tyr403Cys (c.1208A>G) is classified Likely pathogenic in MYO7A (ClinVar, Expert panel, 6 submitters; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9079); Very rare (popmax 8.51e-05%, nfe); Associated with Usher syndrome.

What condition is associated with MYO7A p.Tyr403Cys (c.1208A>G)?

MYO7A p.Tyr403Cys (c.1208A>G) is associated with Usher syndrome, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Tyr403Cys (c.1208A>G) in the general population?

MYO7A p.Tyr403Cys (c.1208A>G) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MYO7A p.Tyr403Cys (c.1208A>G)?

AlphaMissense predicts likely pathogenic (score 0.9079) — an in-silico prediction, not a clinical call.

MYO7A p.Tyr403Cys

c.1208A>G · rs797044511 · VCV178667

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Likely Pathogenic for Usher syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PP1 PP3 PP4 PM3

Curation rationale (ClinGen, verbatim)

The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9079	likely pathogenic ✓ concordant with ClinVar
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -12.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,094 alleles

Overall 6.24e-05% 1/1,602,450 alleles · very rare exomes 0/1,450,376 · genomes 1/152,074 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Tyr403Cys
Coding: c.1208A>G
MANE Select: NM_000260
dbSNP: rs797044511
Type: single nucleotide variant
Location: chr11:77160980 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 403: the myosin motor domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MYO7A p.Tyr403Ter Pathogenic ★ same residue
MYO7A p.Tyr403= Conflicting classifications of pathogenicity ★ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Arg853His Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-tyr403cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown