Is MYO7A p.Ile2133Met (c.6399C>G) pathogenic?

MYO7A p.Ile2133Met (c.6399C>G) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-26). AlphaMissense: likely pathogenic (0.6387); Very rare (popmax 0.00402%, afr); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Ile2133Met (c.6399C>G)?

MYO7A p.Ile2133Met (c.6399C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MYO7A p.Ile2133Met (c.6399C>G) in the general population?

MYO7A p.Ile2133Met (c.6399C>G) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about MYO7A p.Ile2133Met (c.6399C>G)?

AlphaMissense predicts likely pathogenic (score 0.6387) — an in-silico prediction, not a clinical call.

MYO7A p.Ile2133Met

c.6399C>G · rs1957974477 · VCV1471914

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6387	likely pathogenic
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -10.05	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 -1.5	GERP 1.8
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.5	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 0.00402% African / African-American · 3/74,570 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000251% 4/1,594,396 alleles · very rare exomes 3/1,442,276 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,857
European (non-Finnish)	8.55e-05%	1,170,018

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.Ile2133Met
Coding: c.6399C>G
MANE Select: NM_000260
dbSNP: rs1957974477
Type: single nucleotide variant
Location: chr11:77212996 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 2133: the ferm 2 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Ile2133Val Uncertain significance ★ ⚠ same residue
MYO7A p.Ile2133= Likely benign ★ same residue
MYO7A p.Ile2133Asn Uncertain significance ⚠ same residue
MYO7A p.Ser1471Pro Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Ala1005Thr Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1203Ser Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1335Asp Uncertain significance ★★ ⚠ same condition
MYO7A p.Ala1551Val Uncertain significance ★★ ⚠ 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-ile2133met (accessed [today's date]).

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