Is MYO7A p.Leu765Met (c.2293C>A) pathogenic?

MYO7A p.Leu765Met (c.2293C>A) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1408); Ultra-rare (popmax 0.0799%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Leu765Met (c.2293C>A)?

MYO7A p.Leu765Met (c.2293C>A) is associated with Inborn genetic diseases, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Leu765Met (c.2293C>A) in the general population?

MYO7A p.Leu765Met (c.2293C>A) is ultra-rare (popmax 0.0799%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Leu765Met (c.2293C>A)?

AlphaMissense predicts likely benign (score 0.1408) — an in-silico prediction, not a clinical call.

MYO7A p.Leu765Met

c.2293C>A · rs201203036 · VCV43180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1408 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0799%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1408	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.41, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	19.33	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 0.0799% European (non-Finnish) · 940/1,177,088 alleles

Filtering AF 0.0756% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0739%

Overall 0.0611% 981/1,606,472 alleles · ultra-rare exomes 941/1,454,094 · genomes 40/152,378 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0799%	1,252
Remaining individualsnot grpmax-eligible	0.0466%	2,147
African / African-American	0.0133%	7,494
Admixed American	0.00168%	59,412
Finnishnot grpmax-eligible	0.00161%	62,292

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.Leu765Met
Coding: c.2293C>A
MANE Select: NM_000260
dbSNP: rs201203036
Type: single nucleotide variant
Location: chr11:77179055 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 765: the iq 1 domain

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

Disease context

Inborn genetic diseases — 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

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-leu765met (accessed [today's date]).

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