Is USH2A p.Pro4269Arg (c.12806C>G) pathogenic?

USH2A p.Pro4269Arg (c.12806C>G) is classified Likely pathogenic in USH2A (ClinVar, Single submitter, 2 submitters; last evaluated 2021-11-24). AlphaMissense: likely pathogenic (0.7237); Absent from gnomAD v4.1; Associated with USH2A-related disorder.

What condition is associated with USH2A p.Pro4269Arg (c.12806C>G)?

USH2A p.Pro4269Arg (c.12806C>G) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Pro4269Arg (c.12806C>G) in the general population?

USH2A p.Pro4269Arg (c.12806C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USH2A p.Pro4269Arg (c.12806C>G)?

AlphaMissense predicts likely pathogenic (score 0.7237) — an in-silico prediction, not a clinical call.

USH2A p.Pro4269Arg

c.12806C>G · rs1553252475 · VCV555131

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7237 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.7237	likely pathogenic ✓ concordant with ClinVar · top 7% in USH2A
REVEL	0.437	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USH2A
Protein: p.Pro4269Arg
Coding: c.12806C>G
MANE Select: NM_206933
dbSNP: rs1553252475
Type: single nucleotide variant
Location: chr1:215675105 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4269: a UniProt-annotated variant site (in ush2a; uncertain significance); the fibronectin type-iii 28 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

Similar variants

USH2A p.Pro4269His Conflicting classifications of pathogenicity ★ same residue
USH2A p.Pro4269Leu Uncertain significance ★ 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-pro4269arg (accessed [today's date]).

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