Is USH2A p.Ser333Pro (c.997T>C) pathogenic?

USH2A p.Ser333Pro (c.997T>C) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0818); Ultra-rare (popmax 0.0959%, eas); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Ser333Pro (c.997T>C)?

USH2A p.Ser333Pro (c.997T>C) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Ser333Pro (c.997T>C) in the general population?

USH2A p.Ser333Pro (c.997T>C) is ultra-rare (popmax 0.0959%, eas) (gnomAD).

What do computational predictors say about USH2A p.Ser333Pro (c.997T>C)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

USH2A p.Ser333Pro

c.997T>C · rs368986242 · VCV550610

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0959%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

USH2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.608	indeterminate
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP -2.6
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	13.28	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 0.0959% East Asian · 43/44,828 alleles

Filtering AF 0.0732% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0651%

Overall 0.00409% 66/1,613,958 alleles · ultra-rare exomes 57/1,461,672 · genomes 9/152,286 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0959%	1,043
Remaining individualsnot grpmax-eligible	0.0144%	6,944
South Asian	0.011%	9,108
Admixed American	0.00167%	59,974
European (non-Finnish)	0.000254%	393,311

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.Ser333Pro
Coding: c.997T>C
MANE Select: NM_206933
dbSNP: rs368986242
Type: single nucleotide variant
Location: chr1:216325451 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 333: the laminin n-terminal domain

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

Similar variants

USH2A p.Ser333fs Likely pathogenic ★ 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-ser333pro (accessed [today's date]).

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