Is USH1C p.Asp45= (c.135C>T) pathogenic?

USH1C p.Asp45= (c.135C>T) is classified Likely benign in USH1C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-14). Very rare (popmax 0.00833%, amr); Associated with autosomal recessive nonsyndromic hearing loss 18A.

What condition is associated with USH1C p.Asp45= (c.135C>T)?

USH1C p.Asp45= (c.135C>T) is associated with autosomal recessive nonsyndromic hearing loss 18A, Usher syndrome type 1, Usher syndrome type 1C (ClinVar).

How common is USH1C p.Asp45= (c.135C>T) in the general population?

USH1C p.Asp45= (c.135C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

USH1C p.Asp45=

c.135C>T · rs140319839 · VCV741286

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 6	GERP 0.54, phastCons 1
Overall
CADD	11.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,026 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000372% 6/1,613,724 alleles · very rare exomes 6/1,461,486 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,005
European (non-Finnish)	8.47e-05%	1,180,018

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.Asp45=
Coding: c.135C>T
MANE Select: NM_153676
dbSNP: rs140319839
Type: single nucleotide variant
Location: chr11:17531512 (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 45: an α-helix; the 'n-terminal domain' 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 1 Usher syndrome type 1C

Similar variants

USH1C p.Asp45Tyr Pathogenic ★ ⚠ same residue
USH1C p.Asp45Glu 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
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-asp45 (accessed [today's date]).

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