Is CLDN14 p.Cys97Ter (c.291C>A) pathogenic?

CLDN14 p.Cys97Ter (c.291C>A) is classified Pathogenic/Likely pathogenic in CLDN14 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-30). Very rare (popmax 0.00415%, nfe); Associated with CLDN14-related disorders.

What condition is associated with CLDN14 p.Cys97Ter (c.291C>A)?

CLDN14 p.Cys97Ter (c.291C>A) is associated with CLDN14-related disorders, autosomal recessive nonsyndromic hearing loss 29, hearing loss, autosomal recessive (ClinVar).

How common is CLDN14 p.Cys97Ter (c.291C>A) in the general population?

CLDN14 p.Cys97Ter (c.291C>A) is very rare (popmax 0.00415%, nfe) (gnomAD).

CLDN14 p.Cys97Ter

c.291C>A · rs767108790 · VCV3338644

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Conditions

CLDN14-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.018	GERP -4.1, phastCons 0.42
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% European (non-Finnish) · 49/1,179,972 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00316% 51/1,613,008 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,081
Remaining individualsnot grpmax-eligible	0.0032%	31,234

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: CLDN14
Protein: p.Cys97Ter
Coding: c.291C>A
MANE Select: NM_001146079
dbSNP: rs767108790
Type: single nucleotide variant
Location: chr21:36461405 (GRCh38)
Gene constraint: LOEUF 1.745 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 80.00

Full CLDN14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLDN14-related disorders

Also linked: autosomal recessive nonsyndromic hearing loss 29 hearing loss, autosomal recessive

Similar variants

CLDN14 p.Arg81His Pathogenic/Likely pathogenic ★★ same condition
CLDN14 p.Trp30Ter Pathogenic/Likely pathogenic ★★ same condition
CLDN14 c.*107G>A Uncertain significance ★★ same condition
CLDN14 p.Ala196Val Uncertain significance ★★ ⚠ same condition
CLDN14 p.Gly122Ser Uncertain significance ★★ ⚠ same condition
CLDN14 p.Thr179Ala Uncertain significance ★★ ⚠ same condition
CLDN14 c.-290A>G Benign ★★ same condition
CLDN14 c.-82+2024G>A Likely benign ★★ 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/cldn14-p-cys97ter (accessed [today's date]).

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