Is MYO7A p.Glu389Lys (c.1165G>A) pathogenic?

MYO7A p.Glu389Lys (c.1165G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-22). AlphaMissense: likely benign (0.1571); Ultra-rare (popmax 0.0167%, mid); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Glu389Lys (c.1165G>A)?

MYO7A p.Glu389Lys (c.1165G>A) is associated with autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1 (ClinVar).

How common is MYO7A p.Glu389Lys (c.1165G>A) in the general population?

MYO7A p.Glu389Lys (c.1165G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Glu389Lys (c.1165G>A)?

AlphaMissense predicts likely benign (score 0.1571) — an in-silico prediction, not a clinical call.

MYO7A p.Glu389Lys

c.1165G>A · rs782227657 · VCV1016771

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1571 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.1571	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 0.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.3	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 0.0167% Middle Eastern · 1/5,994 alleles

Overall 0.000127% 2/1,578,690 alleles · ultra-rare exomes 2/1,426,346 · genomes 0/152,344 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,994
East Asian	0.00234%	42,662

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.Glu389Lys
Coding: c.1165G>A
MANE Select: NM_000260
dbSNP: rs782227657
Type: single nucleotide variant
Location: chr11:77160247 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 389: the myosin motor domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1

Similar variants

MYO7A p.Glu389Ter Likely pathogenic ★ 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
MYO7A p.Glu968Asp 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-glu389lys (accessed [today's date]).

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