Is CLDN14 p.Ala43= (c.129C>T) pathogenic?

CLDN14 p.Ala43= (c.129C>T) is classified Conflicting classifications of pathogenicity in CLDN14 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0736%, sas); Associated with autosomal recessive nonsyndromic hearing loss 29.

What condition is associated with CLDN14 p.Ala43= (c.129C>T)?

CLDN14 p.Ala43= (c.129C>T) is associated with autosomal recessive nonsyndromic hearing loss 29 (ClinVar).

How common is CLDN14 p.Ala43= (c.129C>T) in the general population?

CLDN14 p.Ala43= (c.129C>T) is ultra-rare (popmax 0.0736%, sas) (gnomAD).

CLDN14 p.Ala43=

c.129C>T · rs150731625 · VCV898996

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, sas)

Conditions

autosomal recessive nonsyndromic hearing loss 29

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 -0.66	GERP -3.1
Overall
CADD	11.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0736% South Asian · 67/90,990 alleles

Filtering AF 0.0594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0543%

Overall 0.0242% 391/1,612,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.311%	322
South Asiangrpmax	0.0736%	1,358
Remaining individualsnot grpmax-eligible	0.0192%	5,204
European (non-Finnish)	0.0183%	5,462
Admixed American	0.00334%	29,970
African / African-American	0.00267%	37,459

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala43=
Coding: c.129C>T
MANE Select: NM_001146079
dbSNP: rs150731625
Type: single nucleotide variant
Location: chr21:36461567 (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

autosomal recessive nonsyndromic hearing loss 29 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLDN14 p.Arg81His Pathogenic/Likely pathogenic ★★ same condition
CLDN14 p.Cys97Ter 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

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-ala43 (accessed [today's date]).

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