Is MYO7A p.Arg654Cys (c.1960C>T) pathogenic?

MYO7A p.Arg654Cys (c.1960C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-02). AlphaMissense: ambiguous (0.4332); Very rare (popmax 0.00953%, nfe); Associated with Usher syndrome type 1B.

What condition is associated with MYO7A p.Arg654Cys (c.1960C>T)?

MYO7A p.Arg654Cys (c.1960C>T) is associated with Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg654Cys (c.1960C>T) in the general population?

MYO7A p.Arg654Cys (c.1960C>T) is very rare (popmax 0.00953%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Arg654Cys (c.1960C>T)?

AlphaMissense predicts ambiguous (score 0.4332) — an in-silico prediction, not a clinical call.

MYO7A p.Arg654Cys

c.1960C>T · rs201928014 · VCV450309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00953%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Usher syndrome type 1B

Computational evidence

Protein change
AlphaMissense	0.4332	ambiguous
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -10.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	33.0	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 0.00953% European (non-Finnish) · 112/1,175,512 alleles

Filtering AF 0.00807% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00755%

Overall 0.00979% 157/1,603,470 alleles · very rare exomes 125/1,451,110 · genomes 32/152,360 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0448%	2,232
Remaining individualsnot grpmax-eligible	0.0113%	8,873
European (non-Finnish)grpmax	0.00953%	10,496
South Asian	0.0056%	17,841
East Asian	0.00451%	22,188
African / African-American	0.00401%	24,953

Finnish 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.Arg654Cys
Coding: c.1960C>T
MANE Select: NM_000260
dbSNP: rs201928014
Type: single nucleotide variant
Location: chr11:77174780 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 654: 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.Arg654His 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-arg654cys (accessed [today's date]).

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