Is USH2A p.Arg3475Ser (c.10425G>T) pathogenic?

USH2A p.Arg3475Ser (c.10425G>T) is classified Uncertain significance in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: ambiguous (0.3441); Very rare (popmax 0.00223%, eas); Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Arg3475Ser (c.10425G>T)?

USH2A p.Arg3475Ser (c.10425G>T) is associated with inherited retinal dystrophy (ClinVar).

How common is USH2A p.Arg3475Ser (c.10425G>T) in the general population?

USH2A p.Arg3475Ser (c.10425G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about USH2A p.Arg3475Ser (c.10425G>T)?

AlphaMissense predicts ambiguous (score 0.3441) — an in-silico prediction, not a clinical call.

USH2A p.Arg3475Ser

c.10425G>T · rs2464394757 · VCV3028682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.3441	ambiguous
REVEL	0.347	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -0.57
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	16.62	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,850 alleles

Overall 6.2e-05% 1/1,613,670 alleles · very rare exomes 1/1,461,534 · genomes 0/152,136 · 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.Arg3475Ser
Coding: c.10425G>T
MANE Select: NM_206933
dbSNP: rs2464394757
Type: single nucleotide variant
Location: chr1:215782898 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3475: the fibronectin type-iii 19 domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A p.Arg3475Lys Uncertain significance ★★ ⚠ same residue
USH2A p.Arg3475Gly Conflicting classifications of pathogenicity ★ same residue
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
USH2A p.Asn346His 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-arg3475ser (accessed [today's date]).

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