Is USH2A p.Ser2639Pro (c.7915T>C) pathogenic?

USH2A p.Ser2639Pro (c.7915T>C) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.9039); Very rare (popmax 0.000169%, nfe); Associated with Usher syndrome.

What condition is associated with USH2A p.Ser2639Pro (c.7915T>C)?

USH2A p.Ser2639Pro (c.7915T>C) is associated with Usher syndrome, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Ser2639Pro (c.7915T>C) in the general population?

USH2A p.Ser2639Pro (c.7915T>C) is very rare (popmax 0.000169%, nfe) (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.Ser2639Pro (c.7915T>C)?

AlphaMissense predicts likely pathogenic (score 0.9039) — an in-silico prediction, not a clinical call.

USH2A p.Ser2639Pro

c.7915T>C · rs398124620 · VCV96667

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9039 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Usher syndrome

Computational evidence

Protein change
AlphaMissense	0.9039	likely pathogenic · top 2% in USH2A
REVEL	0.455	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	23.7	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 0.000169% European (non-Finnish) · 2/1,179,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,058 alleles · very rare exomes 2/1,461,868 · genomes 0/152,190 · 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.Ser2639Pro
Coding: c.7915T>C
MANE Select: NM_206933
dbSNP: rs398124620
Type: single nucleotide variant
Location: chr1:215888734 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2639: a UniProt-annotated variant site (in ush2a; uncertain significance); the fibronectin type-iii 13 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 retinitis pigmentosa 39 retinitis pigmentosa

For Usher syndrome (Orphanet):

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

Similar variants

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
USH2A p.Asn4292Asp 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-ser2639pro (accessed [today's date]).

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