Is USH1C p.Arg63Gln (c.188G>A) pathogenic?

USH1C p.Arg63Gln (c.188G>A) is classified Uncertain significance in USH1C (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-17). AlphaMissense: likely pathogenic (0.8243); Ultra-rare (popmax 0.0201%, eas); Associated with Usher syndrome type 1.

What condition is associated with USH1C p.Arg63Gln (c.188G>A)?

USH1C p.Arg63Gln (c.188G>A) is associated with Usher syndrome type 1, Usher syndrome type 1C, autosomal recessive nonsyndromic hearing loss 18A (ClinVar).

How common is USH1C p.Arg63Gln (c.188G>A) in the general population?

USH1C p.Arg63Gln (c.188G>A) is ultra-rare (popmax 0.0201%, eas) (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 USH1C p.Arg63Gln (c.188G>A)?

AlphaMissense predicts likely pathogenic (score 0.8243) — an in-silico prediction, not a clinical call.

USH1C p.Arg63Gln

c.188G>A · rs372497947 · VCV196417

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8243 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.8243	likely pathogenic
REVEL	0.732	pathogenic-leaning
SaProt	LLR -12.62	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 50 kb · p 0.94 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% East Asian · 9/44,862 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00347% 56/1,614,078 alleles · ultra-rare exomes 50/1,461,812 · genomes 6/152,266 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,985
South Asian	0.00549%	18,212
European (non-Finnish)	0.0033%	30,257
Remaining individualsnot grpmax-eligible	0.0032%	31,252
African / African-American	0.00133%	75,042

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: USH1C
Protein: p.Arg63Gln
Coding: c.188G>A
MANE Select: NM_153676
dbSNP: rs372497947
Type: single nucleotide variant
Location: chr11:17531459 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.51 · 11 PDB
Residue 63: an α-helix; the 'n-terminal domain' region

Full USH1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1C autosomal recessive nonsyndromic hearing loss 18A

For Usher syndrome (Orphanet):

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

Similar variants

USH1C p.Arg63Trp Uncertain significance ★ ⚠ same residue
USH1C p.Arg63= Likely benign ★ same residue
USH1C c.1020-2A>C Likely pathogenic ★★ same condition
USH1C c.104+1G>A Pathogenic/Likely pathogenic ★★ same condition
USH1C c.104+5G>C Likely pathogenic ★★ same condition
USH1C c.105-2A>G Pathogenic/Likely pathogenic ★★ same condition
USH1C c.2185-1G>A Likely pathogenic ★★ same condition
USH1C c.2227-1G>T Pathogenic/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/ush1c-p-arg63gln (accessed [today's date]).

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