Is USH2A p.Arg303Ser (c.907C>A) pathogenic?

USH2A p.Arg303Ser (c.907C>A) is classified Pathogenic/Likely pathogenic in USH2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-16). AlphaMissense: ambiguous (0.5179); Very rare (popmax 0.00334%, amr); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Arg303Ser (c.907C>A)?

USH2A p.Arg303Ser (c.907C>A) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Arg303Ser (c.907C>A) in the general population?

USH2A p.Arg303Ser (c.907C>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about USH2A p.Arg303Ser (c.907C>A)?

AlphaMissense predicts ambiguous (score 0.5179) — an in-silico prediction, not a clinical call.

USH2A p.Arg303Ser

c.907C>A · rs748465849 · VCV1441479

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.5179	ambiguous
REVEL	0.457	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.53, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	22.6	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 0.00334% Admixed American · 2/59,938 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,536 alleles · very rare exomes 5/1,461,348 · genomes 0/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,969
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	8.48e-05%	1,179,722

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.Arg303Ser
Coding: c.907C>A
MANE Select: NM_206933
dbSNP: rs748465849
Type: single nucleotide variant
Location: chr1:216325541 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 303: a UniProt-annotated variant site (in ush2a); the laminin n-terminal 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 Usher syndrome

Similar variants

USH2A p.Arg303His Pathogenic/Likely pathogenic ★★ ⚠ same residue
USH2A p.Arg303Cys Conflicting classifications of pathogenicity ★ same residue
USH2A p.Arg303= Likely benign ★ 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

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-arg303ser (accessed [today's date]).

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