Is USH2A p.Ser2260Pro (c.6778T>C) pathogenic?

USH2A p.Ser2260Pro (c.6778T>C) is classified Uncertain significance in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-11). AlphaMissense: likely pathogenic (0.747); Absent from gnomAD v4.1.

How common is USH2A p.Ser2260Pro (c.6778T>C) in the general population?

USH2A p.Ser2260Pro (c.6778T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USH2A p.Ser2260Pro (c.6778T>C)?

AlphaMissense predicts likely pathogenic (score 0.747) — an in-silico prediction, not a clinical call.

USH2A p.Ser2260Pro

c.6778T>C · VCV4937125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.747 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.747	likely pathogenic · top 7% in USH2A
REVEL	0.313	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USH2A
Protein: p.Ser2260Pro
Coding: c.6778T>C
MANE Select: NM_206933
Type: single nucleotide variant
Location: chr1:215993047 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2260: a UniProt-annotated variant site (in ush2a; uncertain significance); the fibronectin type-iii 9 domain

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

Similar variants

USH2A p.Ser2260Tyr Uncertain significance ★ same residue
USH2A p.Ser2260= Likely benign ★ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same type
USH2A c.8559-2A>G Pathogenic ★★★ same type
USH2A c.8682-9A>G Pathogenic ★★★ same type
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same type
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same type
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same type

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-ser2260pro (accessed [today's date]).

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