Is MYO7A p.Ala1288Pro (c.3862G>C) pathogenic?

MYO7A p.Ala1288Pro (c.3862G>C) is classified Likely pathogenic in MYO7A (ClinVar, Expert panel, 10 submitters; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9978); Very rare (popmax 0.00402%, nfe); Associated with nonsyndromic genetic hearing loss.

What condition is associated with MYO7A p.Ala1288Pro (c.3862G>C)?

MYO7A p.Ala1288Pro (c.3862G>C) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, inherited retinal dystrophy (ClinVar).

How common is MYO7A p.Ala1288Pro (c.3862G>C) in the general population?

MYO7A p.Ala1288Pro (c.3862G>C) is very rare (popmax 0.00402%, nfe) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

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

What do computational predictors say about MYO7A p.Ala1288Pro (c.3862G>C)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

MYO7A p.Ala1288Pro

c.3862G>C · rs749747871 · VCV866837

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

Likely Pathogenic for nonsyndromic genetic deafness. Applied ACMG criteria (verbatim):

PM2_Supporting PM3_Strong PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000260.4:c.3862G>C variant in the MYO7A gene is a missense variant predicted to cause substitution of alanine to proline at amino acid 1288 (p.Ala1288Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (7/110006 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 0.833, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in five individuals with hearing loss or clinical features of Usher syndrome who were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. However, for each individual phase was unknown (PMID: 10094549, 26969326, SCV001533246.2, 2.5 PM3 points) (PM3_Strong, 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_Strong, PM2_Supporting, 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	0.9978	likely pathogenic ✓ concordant with ClinVar · top 5% in MYO7A
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -18.12	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 3.9	GERP 0.64, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.8	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 0.00402% European (non-Finnish) · 47/1,169,706 alleles

Filtering AF 0.0031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00278%

Overall 0.00302% 48/1,591,784 alleles · very rare exomes 40/1,439,870 · genomes 8/151,914 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00402%	24,887
Remaining individualsnot grpmax-eligible	0.00162%	61,770

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.Ala1288Pro
Coding: c.3862G>C
MANE Select: NM_000260
dbSNP: rs749747871
Type: single nucleotide variant
Location: chr11:77190808 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1288: a UniProt-annotated variant site (in ush1b); the ferm 1 domain

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

Disease context

nonsyndromic genetic hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 inherited retinal dystrophy Usher syndrome Usher syndrome type 1B

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MYO7A p.Ala1288Asp Likely pathogenic ★ same residue
MYO7A p.Ala1288Ser Uncertain significance ★ ⚠ same residue
MYO7A p.Ala1288= Likely benign ★★ same residue
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-ala1288pro (accessed [today's date]).

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