Is MYO7A p.Met1781Ile (c.5343G>A) pathogenic?

MYO7A p.Met1781Ile (c.5343G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-06). AlphaMissense: likely pathogenic (0.9834); Very rare (popmax 0.00171%, amr).

How common is MYO7A p.Met1781Ile (c.5343G>A) in the general population?

MYO7A p.Met1781Ile (c.5343G>A) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about MYO7A p.Met1781Ile (c.5343G>A)?

AlphaMissense predicts likely pathogenic (score 0.9834) — an in-silico prediction, not a clinical call.

MYO7A p.Met1781Ile

c.5343G>A · rs1425409546 · VCV1902557

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9834	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -13.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.31	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	27.7	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 0.00171% Admixed American · 1/58,576 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000312% 5/1,601,534 alleles · very rare exomes 5/1,449,234 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,576
European (non-Finnish)	0.000341%	293,582

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.Met1781Ile
Coding: c.5343G>A
MANE Select: NM_000260
dbSNP: rs1425409546
Type: single nucleotide variant
Location: chr11:77204092 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1781: the myth4 2 domain

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

Similar variants

MYO7A p.Met1781Thr Uncertain significance ★ ⚠ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same type
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same type
MYO7A p.Arg668Cys Pathogenic ★★★ same type
MYO7A p.Arg853His Likely pathogenic ★★★ same type
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same type

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-met1781ile (accessed [today's date]).

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