Is USH1C p.Val217= (c.651A>G) pathogenic?

USH1C p.Val217= (c.651A>G) is classified Benign in USH1C (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Common (popmax 8.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 1C.

What condition is associated with USH1C p.Val217= (c.651A>G)?

USH1C p.Val217= (c.651A>G) is associated with Usher syndrome type 1C (ClinVar).

USH1C p.Val217=

Q: How common is USH1C p.Val217= (c.651A>G) in the general population?

USH1C p.Val217= (c.651A>G) is common (popmax 8.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.651A>G · rs75977878 · VCV48021

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 8.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Usher syndrome type 1C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.76	donor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.092	GERP -2.9, phastCons 0.53
Overall
CADD	7.586	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.3% African / African-American · 6,231/75,030 alleles

Filtering AF 8.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.06%

Overall 0.471% 7,598/1,614,004 alleles · common exomes 3,963/1,461,714 · genomes 3,635/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.3%	12
Remaining individualsnot grpmax-eligible	0.653%	153
Admixed American	0.643%	156
Middle Eastern	0.544%	184
Ashkenazi Jewishnot grpmax-eligible	0.311%	322
European (non-Finnish)	0.0368%	2,719
South Asian	0.0154%	6,506

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.Val217=
Coding: c.651A>G
MANE Select: NM_153676
dbSNP: rs75977878
Type: single nucleotide variant
Location: chr11:17526370 (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 217: the pdz 2 domain; a β-strand; the 'mediates interaction with myo7b' region

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

Disease context

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

Similar variants

USH1C p.Val217Ala Uncertain significance ★★ ⚠ same residue
USH1C p.Val217Glu Uncertain significance ★★ ⚠ 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.2227-1G>T Pathogenic/Likely pathogenic ★★ same condition
USH1C c.2280+2T>C Likely pathogenic ★★ same condition
USH1C c.248+1G>A 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-val217 (accessed [today's date]).

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