Is MYO7A p.Ile539Met (c.1617C>G) pathogenic?

MYO7A p.Ile539Met (c.1617C>G) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-16). AlphaMissense: likely benign (0.1067); Very rare (popmax 0.000339%, nfe); Associated with Usher syndrome type 1B.

What condition is associated with MYO7A p.Ile539Met (c.1617C>G)?

MYO7A p.Ile539Met (c.1617C>G) is associated with Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Ile539Met (c.1617C>G) in the general population?

MYO7A p.Ile539Met (c.1617C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Ile539Met (c.1617C>G)?

AlphaMissense predicts likely benign (score 0.1067) — an in-silico prediction, not a clinical call.

MYO7A p.Ile539Met

c.1617C>G · rs782450807 · VCV517298

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Usher syndrome type 1B

Computational evidence

Protein change
AlphaMissense	0.1067	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.8
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	0.802	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000339% European (non-Finnish) · 4/1,179,756 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,628 alleles · very rare exomes 4/1,461,578 · genomes 0/152,050 · 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.Ile539Met
Coding: c.1617C>G
MANE Select: NM_000260
dbSNP: rs782450807
Type: single nucleotide variant
Location: chr11:77162915 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 539: the myosin motor domain

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.Ile539Phe Uncertain significance ★ ⚠ same residue
MYO7A p.Ile539Val Uncertain significance ★ ⚠ same residue
MYO7A p.Ile539= Likely benign ★ 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

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-ile539met (accessed [today's date]).

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