Is MYO7A p.Ile2131Thr (c.6392T>C) pathogenic?

MYO7A p.Ile2131Thr (c.6392T>C) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-31). AlphaMissense: likely pathogenic (0.9134); Very rare (popmax 0.00154%, nfe); Associated with Usher syndrome type 1B.

What condition is associated with MYO7A p.Ile2131Thr (c.6392T>C)?

MYO7A p.Ile2131Thr (c.6392T>C) is associated with Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Ile2131Thr (c.6392T>C) in the general population?

MYO7A p.Ile2131Thr (c.6392T>C) is very rare (popmax 0.00154%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Ile2131Thr (c.6392T>C)?

AlphaMissense predicts likely pathogenic (score 0.9134) — an in-silico prediction, not a clinical call.

MYO7A p.Ile2131Thr

c.6392T>C · rs1214326316 · VCV965122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00154%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1B

Computational evidence

Protein change
AlphaMissense	0.9134	likely pathogenic
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -11.91	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 7.9	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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00154% European (non-Finnish) · 18/1,170,758 alleles

Filtering AF 0.000961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000793%

Overall 0.00113% 18/1,595,978 alleles · very rare exomes 18/1,443,724 · genomes 0/152,254 · joint denominator

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.Ile2131Thr
Coding: c.6392T>C
MANE Select: NM_000260
dbSNP: rs1214326316
Type: single nucleotide variant
Location: chr11:77212989 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 2131: the ferm 2 domain; a β-strand

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

Disease context

Usher syndrome type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Ile2131Ser Uncertain significance ★ ⚠ 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-ile2131thr (accessed [today's date]).

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