Is USH2A p.Phe595Ser (c.1784T>C) pathogenic?

USH2A p.Phe595Ser (c.1784T>C) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-12). AlphaMissense: likely benign (0.0439); Rare (popmax 0.113%, amr); Associated with Inborn genetic diseases.

What condition is associated with USH2A p.Phe595Ser (c.1784T>C)?

USH2A p.Phe595Ser (c.1784T>C) is associated with Inborn genetic diseases (ClinVar).

How common is USH2A p.Phe595Ser (c.1784T>C) in the general population?

USH2A p.Phe595Ser (c.1784T>C) is rare (popmax 0.113%, amr) (gnomAD).

What do computational predictors say about USH2A p.Phe595Ser (c.1784T>C)?

AlphaMissense predicts likely benign (score 0.0439) — an in-silico prediction, not a clinical call.

USH2A p.Phe595Ser

c.1784T>C · rs200496467 · VCV179735

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0439 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0439	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.40	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 -1.1	GERP -2.4
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	4.967	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 0.113% Admixed American · 68/60,028 alleles

Filtering AF 0.0917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0838%

Overall 0.00533% 86/1,614,088 alleles · rare exomes 33/1,461,790 · genomes 53/152,298 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.113%	883
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-American	0.00266%	37,526
European (non-Finnish)	0.000593%	168,564

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.Phe595Ser
Coding: c.1784T>C
MANE Select: NM_206933
dbSNP: rs200496467
Type: single nucleotide variant
Location: chr1:216292231 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 595: a UniProt-annotated variant site (in); the laminin egf-like 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A p.Gln4900Ter Pathogenic/Likely pathogenic ★★ same condition
USH2A p.Ala1617Val Uncertain significance ★★ same condition
USH2A p.Ala1877Glu Uncertain significance ★★ same condition
USH2A p.Ala1952Val Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2111Glu Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2234Val Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2246Asp Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2459Gly Uncertain significance ★★ ⚠ 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-phe595ser (accessed [today's date]).

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