Is MYO7A p.Ala826Thr (c.2476G>A) pathogenic?

MYO7A p.Ala826Thr (c.2476G>A) is classified Uncertain significance in MYO7A (ClinVar, Expert panel, 16 submitters; last evaluated 2023-01-18). AlphaMissense: likely benign (0.2855); Rare (popmax 0.601%, sas); Associated with Usher syndrome.

What condition is associated with MYO7A p.Ala826Thr (c.2476G>A)?

MYO7A p.Ala826Thr (c.2476G>A) is associated with Usher syndrome, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Ala826Thr (c.2476G>A) in the general population?

MYO7A p.Ala826Thr (c.2476G>A) is rare (popmax 0.601%, sas) (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.Ala826Thr (c.2476G>A)?

AlphaMissense predicts likely benign (score 0.2855) — an in-silico prediction, not a clinical call.

MYO7A p.Ala826Thr

c.2476G>A · rs368341987 · VCV177732

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.2855 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.601%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Uncertain Significance for Usher syndrome. Applied ACMG criteria (verbatim):

PP1_Strong PP4 PM3_Strong BA1

Curation rationale (ClinGen, verbatim)

The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023).

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

Computational evidence

Protein change
AlphaMissense	0.2855	likely benign
REVEL	0.54	indeterminate
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.601% South Asian · 505/84,020 alleles

Filtering AF 0.558% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.54%

Overall 0.0683% 1,053/1,542,830 alleles · rare exomes 989/1,390,456 · genomes 64/152,374 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.601%	166
Remaining individualsnot grpmax-eligible	0.0717%	1,395
Middle Eastern	0.0542%	1,843
European (non-Finnish)	0.0425%	2,355
Admixed American	0.0098%	10,209
African / African-American	0.00957%	10,453
East Asian	0.00733%	13,646

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.Ala826Thr
Coding: c.2476G>A
MANE Select: NM_000260
dbSNP: rs368341987
Type: single nucleotide variant
Location: chr11:77179843 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 826: the iq 4 domain; a UniProt-annotated variant site (in ush1b; uncertain significance)

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 autosomal dominant nonsyndromic hearing loss 11 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-ala826thr (accessed [today's date]).

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