Is USH2A p.Val3003Ala (c.9008T>C) pathogenic?

USH2A p.Val3003Ala (c.9008T>C) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1047); Rare (popmax 0.413%, mid); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Val3003Ala (c.9008T>C)?

USH2A p.Val3003Ala (c.9008T>C) is associated with Usher syndrome type 2A (ClinVar).

How common is USH2A p.Val3003Ala (c.9008T>C) in the general population?

USH2A p.Val3003Ala (c.9008T>C) is rare (popmax 0.413%, mid) (gnomAD).

What do computational predictors say about USH2A p.Val3003Ala (c.9008T>C)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

USH2A p.Val3003Ala

c.9008T>C · rs138574386 · VCV286068

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.413%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -3.8, phastCons 0.018
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	14.56	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 0.413% Middle Eastern · 25/6,046 alleles

Filtering AF 0.287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.246%

Overall 0.018% 291/1,613,746 alleles · rare exomes 268/1,461,590 · genomes 23/152,156 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.413%	242
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)	0.0193%	5,175
Admixed American	0.0184%	5,445
African / African-American	0.004%	24,989
South Asian	0.00329%	30,359

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.Val3003Ala
Coding: c.9008T>C
MANE Select: NM_206933
dbSNP: rs138574386
Type: single nucleotide variant
Location: chr1:215845871 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3003: the fibronectin type-iii 16 domain

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

Disease context

Usher syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A p.Val3003= 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
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-val3003ala (accessed [today's date]).

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