Is USH2A p.Pro1076Ser (c.3226C>T) pathogenic?

USH2A p.Pro1076Ser (c.3226C>T) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-09-13). AlphaMissense: likely benign (0.1509); Ultra-rare (popmax 0.0281%, nfe); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Pro1076Ser (c.3226C>T)?

USH2A p.Pro1076Ser (c.3226C>T) is associated with Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Pro1076Ser (c.3226C>T) in the general population?

USH2A p.Pro1076Ser (c.3226C>T) is ultra-rare (popmax 0.0281%, nfe) (gnomAD).

What do computational predictors say about USH2A p.Pro1076Ser (c.3226C>T)?

AlphaMissense predicts likely benign (score 0.1509) — an in-silico prediction, not a clinical call.

USH2A p.Pro1076Ser

c.3226C>T · rs139089840 · VCV848666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1509 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, nfe)

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.1509	likely benign
REVEL	0.322	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	23.5	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 0.0281% European (non-Finnish) · 332/1,179,966 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.0213% 343/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0281%	3,554
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.004%	25,017

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.Pro1076Ser
Coding: c.3226C>T
dbSNP: rs139089840
Type: single nucleotide variant
Location: chr1:216207363 (GRCh38)

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

Disease context

Usher syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 39

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-pro1076ser (accessed [today's date]).

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