Is USH2A p.Arg317= (c.949C>A) pathogenic?

USH2A p.Arg317= (c.949C>A) is classified Pathogenic in USH2A (ClinVar, Multiple submitters, 21 submitters; last evaluated 2026-07-20). Very rare (popmax 0.00542%, nfe); Associated with Monogenic hearing loss.

What condition is associated with USH2A p.Arg317= (c.949C>A)?

USH2A p.Arg317= (c.949C>A) is associated with Monogenic hearing loss, blindness (disorder), Usher syndrome type 2A (ClinVar).

How common is USH2A p.Arg317= (c.949C>A) in the general population?

USH2A p.Arg317= (c.949C>A) is very rare (popmax 0.00542%, nfe) (gnomAD).

USH2A p.Arg317=

c.949C>A · rs111033272 · VCV2358

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Conditions

Monogenic hearing loss

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.73	donor gain · deltas
Pangolin	Δ0.50	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.6	GERP -0.32, phastCons 0.92
Overall
CADD	18.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00542% European (non-Finnish) · 64/1,179,902 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00421% 68/1,613,720 alleles · very rare exomes 65/1,461,598 · genomes 3/152,122 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)grpmax	0.00542%	18,436

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg317=
Coding: c.949C>A
MANE Select: NM_206933
dbSNP: rs111033272
Type: single nucleotide variant
Location: chr1:216325499 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 317: the laminin n-terminal domain

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

Disease context

Monogenic hearing loss

Also linked: blindness (disorder)Usher syndrome type 2A retinitis pigmentosa 39 Usher syndrome type 2 inherited retinal dystrophy

Similar variants

USH2A p.Arg317Gln Uncertain significance ★★ ⚠ same residue
USH2A p.Arg317Trp 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-arg317 (accessed [today's date]).

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