Is USH2A p.Cys577Arg (c.1729T>C) pathogenic?

USH2A p.Cys577Arg (c.1729T>C) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9522); Very rare (popmax 8.47e-05%, nfe); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Cys577Arg (c.1729T>C)?

USH2A p.Cys577Arg (c.1729T>C) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Cys577Arg (c.1729T>C) in the general population?

USH2A p.Cys577Arg (c.1729T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about USH2A p.Cys577Arg (c.1729T>C)?

AlphaMissense predicts likely pathogenic (score 0.9522) — an in-silico prediction, not a clinical call.

USH2A p.Cys577Arg

c.1729T>C · rs1553327470 · VCV553101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.9522	likely pathogenic · top 1% in USH2A
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -17.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	23.8	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 8.47e-05% European (non-Finnish) · 1/1,179,980 alleles

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 1/1,461,788 · genomes 0/152,334 · 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: USH2A
Protein: p.Cys577Arg
Coding: c.1729T>C
MANE Select: NM_206933
dbSNP: rs1553327470
Type: single nucleotide variant
Location: chr1:216292286 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 577: a disulfide bond; the laminin egf-like 2 domain

Full USH2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Usher syndrome type 2A retinitis pigmentosa 39 inherited retinal dystrophy

Similar variants

USH2A p.Cys577= Benign/Likely benign ★★ same residue
USH2A p.Cys577Tyr Likely pathogenic ★ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same condition
USH2A c.8559-2A>G Pathogenic ★★★ same condition
USH2A c.8682-9A>G Pathogenic ★★★ same condition
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same condition
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same condition
USH2A p.Arg4192Cys 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/ush2a-p-cys577arg (accessed [today's date]).

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