Is USH2A p.Val4523Phe (c.13567G>T) pathogenic?

USH2A p.Val4523Phe (c.13567G>T) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-16). AlphaMissense: likely benign (0.1358); Very rare (popmax 0.00254%, nfe); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Val4523Phe (c.13567G>T)?

USH2A p.Val4523Phe (c.13567G>T) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Val4523Phe (c.13567G>T) in the general population?

USH2A p.Val4523Phe (c.13567G>T) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about USH2A p.Val4523Phe (c.13567G>T)?

AlphaMissense predicts likely benign (score 0.1358) — an in-silico prediction, not a clinical call.

USH2A p.Val4523Phe

c.13567G>T · rs746442849 · VCV865805

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.1358	likely benign
REVEL	0.146	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 0.54	GERP -0.29, phastCons 0.032
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	13.59	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 0.00254% European (non-Finnish) · 30/1,179,842 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00204% 33/1,613,844 alleles · very rare exomes 33/1,461,666 · genomes 0/152,178 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,833
European (non-Finnish)grpmax	0.00254%	39,328

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val4523Phe
Coding: c.13567G>T
MANE Select: NM_206933
dbSNP: rs746442849
Type: single nucleotide variant
Location: chr1:215674344 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4523: the fibronectin type-iii 30 domain; the 'disordered' region

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.Val4523Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
USH2A p.Val4523= 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

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-val4523phe (accessed [today's date]).

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