Is USH2A p.Pro4287Ser (c.12859C>T) pathogenic?

USH2A p.Pro4287Ser (c.12859C>T) is classified Uncertain significance in USH2A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely benign (0.1151); Absent from gnomAD v4.1; Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Pro4287Ser (c.12859C>T)?

USH2A p.Pro4287Ser (c.12859C>T) is associated with Usher syndrome type 2A (ClinVar).

How common is USH2A p.Pro4287Ser (c.12859C>T) in the general population?

USH2A p.Pro4287Ser (c.12859C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USH2A p.Pro4287Ser (c.12859C>T)?

AlphaMissense predicts likely benign (score 0.1151) — an in-silico prediction, not a clinical call.

USH2A p.Pro4287Ser

c.12859C>T · VCV4062750

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1151 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.1151	likely benign
REVEL	0.262	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	17.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Pro4287Ser
Coding: c.12859C>T
MANE Select: NM_206933
Type: single nucleotide variant
Location: chr1:215675052 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4287: the fibronectin type-iii 28 domain

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

Similar variants

USH2A p.Pro4287fs Pathogenic/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-pro4287ser (accessed [today's date]).

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