Is MYO7A p.Ala397Thr (c.1189G>A) pathogenic?

MYO7A p.Ala397Thr (c.1189G>A) is classified Pathogenic/Likely pathogenic in MYO7A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-12). AlphaMissense: likely pathogenic (0.9255); Very rare (popmax 0.00188%, amr); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Ala397Thr (c.1189G>A)?

MYO7A p.Ala397Thr (c.1189G>A) is associated with MYO7A-related disorder, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Ala397Thr (c.1189G>A) in the general population?

MYO7A p.Ala397Thr (c.1189G>A) is very rare (popmax 0.00188%, amr) (gnomAD).

What do computational predictors say about MYO7A p.Ala397Thr (c.1189G>A)?

AlphaMissense predicts likely pathogenic (score 0.9255) — an in-silico prediction, not a clinical call.

MYO7A p.Ala397Thr

c.1189G>A · rs1297886521 · VCV554214

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00188%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.9255	likely pathogenic ✓ concordant with ClinVar
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -11.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	27.1	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 0.00188% Admixed American · 1/53,116 alleles

Filtering AF 0.000298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000215%

Overall 0.000703% 11/1,564,278 alleles · very rare exomes 11/1,411,928 · genomes 0/152,350 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00695%	14,389
Admixed Americangrpmax	0.00188%	53,116
European (non-Finnish)	0.000693%	144,400

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala397Thr
Coding: c.1189G>A
MANE Select: NM_000260
dbSNP: rs1297886521
Type: single nucleotide variant
Location: chr11:77160271 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 397: the myosin motor domain; a UniProt-annotated variant site (in ush1b)

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

Disease context

MYO7A-related disorder

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.Ala397Asp Pathogenic/Likely pathogenic ★★ same residue
MYO7A p.Ala397= Likely benign ★★ same residue
MYO7A p.Ala397Gly Likely pathogenic ★ ⚠ same residue
MYO7A p.Ala397Val Likely pathogenic ★ same residue
MYO7A p.Ala397Ser Uncertain significance ★ ⚠ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln 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-ala397thr (accessed [today's date]).

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