Is USH2A p.Cys985Arg (c.2953T>C) pathogenic?

USH2A p.Cys985Arg (c.2953T>C) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-18). AlphaMissense: likely pathogenic (0.9024); Very rare (popmax 0.00267%, afr); Associated with Usher syndrome.

What condition is associated with USH2A p.Cys985Arg (c.2953T>C)?

USH2A p.Cys985Arg (c.2953T>C) is associated with Usher syndrome, retinitis pigmentosa 39, retinitis pigmentosa (ClinVar).

How common is USH2A p.Cys985Arg (c.2953T>C) in the general population?

USH2A p.Cys985Arg (c.2953T>C) is very rare (popmax 0.00267%, afr) (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.Cys985Arg (c.2953T>C)?

AlphaMissense predicts likely pathogenic (score 0.9024) — an in-silico prediction, not a clinical call.

USH2A p.Cys985Arg

c.2953T>C · rs1171264735 · VCV623722

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.9024	likely pathogenic
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -15.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	21.8	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

Grpmax group 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,613,936 alleles · very rare exomes 6/1,461,732 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,462
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000424%	235,987

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.Cys985Arg
Coding: c.2953T>C
MANE Select: NM_206933
dbSNP: rs1171264735
Type: single nucleotide variant
Location: chr1:216231993 (GRCh38)

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: retinitis pigmentosa 39 retinitis pigmentosa

For Usher syndrome (Orphanet):

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

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-cys985arg (accessed [today's date]).

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