Is USH1C p.Ser708= (c.2124T>C) pathogenic?

USH1C p.Ser708= (c.2124T>C) is classified Conflicting classifications of pathogenicity in USH1C (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-04-17). Ultra-rare (popmax 0.0977%, sas); Associated with Usher syndrome type 1C.

What condition is associated with USH1C p.Ser708= (c.2124T>C)?

USH1C p.Ser708= (c.2124T>C) is associated with Usher syndrome type 1C, autosomal recessive nonsyndromic hearing loss 18A (ClinVar).

How common is USH1C p.Ser708= (c.2124T>C) in the general population?

USH1C p.Ser708= (c.2124T>C) is ultra-rare (popmax 0.0977%, sas) (gnomAD).

USH1C p.Ser708=

c.2124T>C · rs369021714 · VCV228194

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0977%, sas)

Conditions

Usher syndrome type 1C

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 -4.6	GERP -4.2
Overall
CADD	0.521	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0977% South Asian · 89/91,068 alleles

Filtering AF 0.0813% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.0175% 283/1,613,970 alleles · ultra-rare exomes 269/1,461,750 · genomes 14/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0977%	1,023
Middle Eastern	0.0164%	6,082
European (non-Finnish)	0.0157%	6,378
Remaining individualsnot grpmax-eligible	0.0096%	10,413
Admixed American	0.00167%	60,008
African / African-American	0.00133%	74,922

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.Ser708=
Coding: c.2124T>C
MANE Select: NM_153676
dbSNP: rs369021714
Type: single nucleotide variant
Location: chr11:17505839 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.51 · 11 PDB

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.Ser708Pro 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
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-ser708 (accessed [today's date]).

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