Is USH2A p.Val164Ala (c.491T>C) pathogenic?

USH2A p.Val164Ala (c.491T>C) is classified Uncertain significance in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-17). AlphaMissense: ambiguous (0.4455); Very rare (popmax 0.00223%, eas).

How common is USH2A p.Val164Ala (c.491T>C) in the general population?

USH2A p.Val164Ala (c.491T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about USH2A p.Val164Ala (c.491T>C)?

AlphaMissense predicts ambiguous (score 0.4455) — an in-silico prediction, not a clinical call.

USH2A p.Val164Ala

c.491T>C · VCV4940190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4455	ambiguous
REVEL	0.134	moderately benign-leaning
SaProt	LLR -7.47	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,766 alleles

Overall 0.000124% 2/1,612,926 alleles · very rare exomes 2/1,460,762 · genomes 0/152,164 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,766
African / African-American	0.00133%	74,940

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.Val164Ala
Coding: c.491T>C
MANE Select: NM_206933
Type: single nucleotide variant
Location: chr1:216418674 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Similar variants

USH2A p.Val164Phe Pathogenic/Likely pathogenic ★★ ⚠ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same type
USH2A c.8559-2A>G Pathogenic ★★★ same type
USH2A c.8682-9A>G Pathogenic ★★★ same type
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same type
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same type
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same type
USH2A p.Asn346His Pathogenic ★★★ same type

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-val164ala (accessed [today's date]).

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