Is USH2A p.Ala3573Pro (c.10717G>C) pathogenic?

USH2A p.Ala3573Pro (c.10717G>C) is classified Uncertain significance in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-20). AlphaMissense: ambiguous (0.4187); Very rare (popmax 0.00167%, amr); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Ala3573Pro (c.10717G>C)?

USH2A p.Ala3573Pro (c.10717G>C) is associated with USH2A-related disorder (ClinVar).

How common is USH2A p.Ala3573Pro (c.10717G>C) in the general population?

USH2A p.Ala3573Pro (c.10717G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about USH2A p.Ala3573Pro (c.10717G>C)?

AlphaMissense predicts ambiguous (score 0.4187) — an in-silico prediction, not a clinical call.

USH2A p.Ala3573Pro

c.10717G>C · VCV4293990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.4187	ambiguous
REVEL	0.242	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.82	GERP 0.97, phastCons 0.002
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	18.87	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 0.00167% Admixed American · 1/60,008 alleles

Overall 6.2e-05% 1/1,613,906 alleles · very rare exomes 0/1,461,700 · genomes 1/152,206 · 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.Ala3573Pro
Coding: c.10717G>C
MANE Select: NM_206933
Type: single nucleotide variant
Location: chr1:215782065 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3573: the fibronectin type-iii 20 domain

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

Disease context

USH2A-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A c.10183-2A>G Pathogenic/Likely pathogenic ★★ same condition
USH2A c.10387+1G>A Likely pathogenic ★★ same condition
USH2A c.11047+1G>A Pathogenic/Likely pathogenic ★★ same condition
USH2A c.11048-2A>G Pathogenic/Likely pathogenic ★★ same condition
USH2A c.11712-2A>G Likely pathogenic ★★ same condition
USH2A c.14344-1G>T Pathogenic ★★ same condition
USH2A c.14582+1G>C Pathogenic/Likely pathogenic ★★ same condition
USH2A c.14791+2T>A Pathogenic/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-ala3573pro (accessed [today's date]).

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