Is MYO7A p.Met283Ile (c.849G>A) pathogenic?

MYO7A p.Met283Ile (c.849G>A) is classified Likely pathogenic in MYO7A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-04). AlphaMissense: ambiguous (0.3496); Very rare (popmax 0.00017%, nfe); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Met283Ile (c.849G>A)?

MYO7A p.Met283Ile (c.849G>A) is associated with MYO7A-related disorder (ClinVar).

How common is MYO7A p.Met283Ile (c.849G>A) in the general population?

MYO7A p.Met283Ile (c.849G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Met283Ile (c.849G>A)?

AlphaMissense predicts ambiguous (score 0.3496) — an in-silico prediction, not a clinical call.

MYO7A p.Met283Ile

c.849G>A · rs1280774223 · VCV1052282

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3496 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.3496	ambiguous
REVEL	0.392	indeterminate
SaProt	LLR -8.08	tolerated
Splicing
SpliceAI	Δ0.64	donor loss · deltas
Pangolin	Δ0.71	loss · gain 0.46 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	31.0	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 0.00017% European (non-Finnish) · 2/1,173,764 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,601,450 alleles · very rare exomes 1/1,449,280 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,098
European (non-Finnish)grpmax	0.00017%	586,882

Remaining individuals 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.Met283Ile
Coding: c.849G>A
MANE Select: NM_000260
dbSNP: rs1280774223
Type: single nucleotide variant
Location: chr11:77157392 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 283: the myosin motor domain

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

Disease context

MYO7A-related disorder

Similar variants

MYO7A c.133-2A>G Pathogenic ★★ same condition
MYO7A c.1344-2A>G Pathogenic ★★ same condition
MYO7A c.1690+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.18+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.19-1G>A Likely pathogenic ★★ same condition
MYO7A c.2187+1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.2283-1G>A Pathogenic/Likely pathogenic ★★ same condition
MYO7A c.2694+1G>A 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-met283ile (accessed [today's date]).

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