Is USH1C p.Pro396= (c.1188A>G) pathogenic?

USH1C p.Pro396= (c.1188A>G) is classified Benign in USH1C (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 67.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 18A.

What condition is associated with USH1C p.Pro396= (c.1188A>G)?

USH1C p.Pro396= (c.1188A>G) is associated with autosomal recessive nonsyndromic hearing loss 18A, Usher syndrome type 1C (ClinVar).

USH1C p.Pro396=

Q: How common is USH1C p.Pro396= (c.1188A>G) in the general population?

USH1C p.Pro396= (c.1188A>G) is common (popmax 67.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1188A>G · rs2240487 · VCV47976

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 67.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive nonsyndromic hearing loss 18A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.8	GERP -5.1
Overall
CADD	0.985	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.3% East Asian · 30,175/44,862 alleles

Filtering AF 66.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.4%

Overall 57.5% 927,980/1,613,522 alleles · common exomes 848,790/1,461,484 · genomes 79,190/152,038 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	67.3%	1
Admixed American	65%	2
Amishnot grpmax-eligible	64.6%	2
European (non-Finnish)	58.7%	2
Ashkenazi Jewishnot grpmax-eligible	57.8%	2
Finnishnot grpmax-eligible	57.1%	2
Remaining individualsnot grpmax-eligible	56.8%	2
South Asian	52.3%	2
Middle Eastern	50.1%	2
African / African-American	34%	3

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.Pro396=
Coding: c.1188A>G
MANE Select: NM_153676
dbSNP: rs2240487
Type: single nucleotide variant
Location: chr11:17520892 (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 396: the 'mediates interaction with myo7b' region

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

Disease context

autosomal recessive nonsyndromic hearing loss 18A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1C

Similar variants

USH1C p.Pro396Ala Uncertain significance ★ ⚠ same residue
USH1C p.Pro396Leu Uncertain significance ★★ same residue
USH1C p.Pro396Arg 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.105-2A>G Pathogenic/Likely pathogenic ★★ same condition
USH1C c.2185-1G>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-pro396 (accessed [today's date]).

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