Is USH2A p.Val164Phe (c.490G>T) pathogenic?

USH2A p.Val164Phe (c.490G>T) is classified Pathogenic/Likely pathogenic in USH2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.2459); Very rare (popmax 0.0067%, eas); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Val164Phe (c.490G>T)?

USH2A p.Val164Phe (c.490G>T) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Val164Phe (c.490G>T) in the general population?

USH2A p.Val164Phe (c.490G>T) is very rare (popmax 0.0067%, eas) (gnomAD).

What do computational predictors say about USH2A p.Val164Phe (c.490G>T)?

AlphaMissense predicts likely benign (score 0.2459) — an in-silico prediction, not a clinical call.

USH2A p.Val164Phe

c.490G>T · rs527236123 · VCV143182

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.2459	likely benign ⚠ discordant with ClinVar
REVEL	0.271	benign-leaning
SaProt	LLR -7.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -0.089
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	15.74	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 0.0067% East Asian · 3/44,750 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000893%

Overall 0.000186% 3/1,612,888 alleles · very rare exomes 3/1,460,750 · genomes 0/152,138 · 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.Val164Phe
Coding: c.490G>T
MANE Select: NM_206933
dbSNP: rs527236123
Type: single nucleotide variant
Location: chr1:216418675 (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

Disease context

Also linked: Usher syndrome type 2A retinitis pigmentosa 39 inherited retinal dystrophy retinitis pigmentosa

Similar variants

USH2A p.Val164Ala 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
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-val164phe (accessed [today's date]).

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