Is MYO7A p.Asp1266Gly (c.3797A>G) pathogenic?

MYO7A p.Asp1266Gly (c.3797A>G) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 3 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.976); Very rare (popmax 0.0094%, afr); Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Asp1266Gly (c.3797A>G)?

MYO7A p.Asp1266Gly (c.3797A>G) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Asp1266Gly (c.3797A>G) in the general population?

MYO7A p.Asp1266Gly (c.3797A>G) is very rare (popmax 0.0094%, afr) (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.Asp1266Gly (c.3797A>G)?

AlphaMissense predicts likely pathogenic (score 0.976) — an in-silico prediction, not a clinical call.

MYO7A p.Asp1266Gly

c.3797A>G · rs781670345 · VCV557841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0094%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.976	likely pathogenic
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -13.37	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 7	GERP -2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0094% African / African-American · 7/74,488 alleles

Filtering AF 0.0044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.0005% 8/1,599,666 alleles · very rare exomes 4/1,447,920 · genomes 4/151,746 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0094%	10,641
European (non-Finnish)	8.52e-05%	1,173,658

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.Asp1266Gly
Coding: c.3797A>G
MANE Select: NM_000260
dbSNP: rs781670345
Type: single nucleotide variant
Location: chr11:77190743 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1266: the ferm 1 domain

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

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Usher syndrome (Orphanet):

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

Similar variants

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
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Gly2187Asp 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-asp1266gly (accessed [today's date]).

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