Is USH1C p.Pro516= (c.1548G>A) pathogenic?

USH1C p.Pro516= (c.1548G>A) is classified Likely benign in USH1C (ClinVar, Single submitter, 2 submitters; last evaluated 2016-02-23). Ultra-rare (popmax 0.0169%, mid); Associated with Usher syndrome type 1C.

What condition is associated with USH1C p.Pro516= (c.1548G>A)?

USH1C p.Pro516= (c.1548G>A) is associated with Usher syndrome type 1C, autosomal recessive nonsyndromic hearing loss 18A (ClinVar).

How common is USH1C p.Pro516= (c.1548G>A) in the general population?

USH1C p.Pro516= (c.1548G>A) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

USH1C p.Pro516=

c.1548G>A · rs780428813 · VCV228193

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Conditions

Usher syndrome type 1C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -14	GERP -5.2
Overall
CADD	0.333	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,916 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.00147% 23/1,565,912 alleles · ultra-rare exomes 18/1,416,182 · genomes 5/149,730 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,916
Admixed American	0.0069%	14,489
African / African-American	0.00682%	14,653
South Asian	0.00341%	29,305
Remaining individualsnot grpmax-eligible	0.0033%	30,323
European (non-Finnish)	0.00069%	144,958

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.Pro516=
Coding: c.1548G>A
MANE Select: NM_153676
dbSNP: rs780428813
Type: single nucleotide variant
Location: chr11:17509821 (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 516: the pdz 3 domain; the 'mediates interaction with myo7b' region; an α-helix

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

Also linked: autosomal recessive nonsyndromic hearing loss 18A

Similar variants

USH1C p.Pro516Leu Conflicting classifications of pathogenicity ★ 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
USH1C c.2280+2T>C 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-pro516 (accessed [today's date]).

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