Is USH2A p.Cys717Ser (c.2149T>A) pathogenic?

USH2A p.Cys717Ser (c.2149T>A) is classified Pathogenic in USH2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-08). AlphaMissense: likely pathogenic (0.956); Absent from gnomAD v4.1; Associated with Usher syndrome.

What condition is associated with USH2A p.Cys717Ser (c.2149T>A)?

USH2A p.Cys717Ser (c.2149T>A) is associated with Usher syndrome, Usher syndrome type 2A (ClinVar).

How common is USH2A p.Cys717Ser (c.2149T>A) in the general population?

USH2A p.Cys717Ser (c.2149T>A) is absent from gnomAD v4.1 (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about USH2A p.Cys717Ser (c.2149T>A)?

AlphaMissense predicts likely pathogenic (score 0.956) — an in-silico prediction, not a clinical call.

USH2A p.Cys717Ser

c.2149T>A · rs1304016981 · VCV954433

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

Computational evidence

Protein change
AlphaMissense	0.956	likely pathogenic ✓ concordant with ClinVar · top 1% in USH2A
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -13.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.3, 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 and SaProt are independent agreement signals.

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.Cys717Ser
Coding: c.2149T>A
MANE Select: NM_206933
dbSNP: rs1304016981
Type: single nucleotide variant
Location: chr1:216250921 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 717: a disulfide bond; the laminin egf-like 4 domain

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

Disease context

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

Also linked: Usher syndrome type 2A

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

USH2A p.Cys717Gly Pathogenic/Likely pathogenic ★★ same residue
USH2A p.Cys717Arg Uncertain significance ★ ⚠ 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

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-cys717ser (accessed [today's date]).

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