Is USH2A p.Pro341Ser (c.1021C>T) pathogenic?

USH2A p.Pro341Ser (c.1021C>T) is classified Uncertain significance in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1972); Very rare (popmax 0.000424%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Pro341Ser (c.1021C>T)?

USH2A p.Pro341Ser (c.1021C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is USH2A p.Pro341Ser (c.1021C>T) in the general population?

USH2A p.Pro341Ser (c.1021C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about USH2A p.Pro341Ser (c.1021C>T)?

AlphaMissense predicts likely benign (score 0.1972) — an in-silico prediction, not a clinical call.

USH2A p.Pro341Ser

c.1021C>T · rs2037710415 · VCV3028748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1972	likely benign
REVEL	0.763	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	24.3	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 0.000424% European (non-Finnish) · 5/1,179,914 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,874 alleles · very rare exomes 5/1,461,680 · genomes 0/152,194 · 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.Pro341Ser
Coding: c.1021C>T
MANE Select: NM_206933
dbSNP: rs2037710415
Type: single nucleotide variant
Location: chr1:216325427 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 341: the laminin n-terminal domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
USH2A p.Asn4292Asp Likely pathogenic ★★★ ⚠ same condition
USH2A p.Cys759Phe 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-pro341ser (accessed [today's date]).

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