Is CDC14A p.Arg376Ter (c.1126C>T) pathogenic?

CDC14A p.Arg376Ter (c.1126C>T) is classified Pathogenic/Likely pathogenic in CDC14A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-07-10). Ultra-rare (popmax 0.0172%, mid); Associated with autosomal recessive nonsyndromic hearing loss 32.

What condition is associated with CDC14A p.Arg376Ter (c.1126C>T)?

CDC14A p.Arg376Ter (c.1126C>T) is associated with autosomal recessive nonsyndromic hearing loss 32, ear malformation (ClinVar).

How common is CDC14A p.Arg376Ter (c.1126C>T) in the general population?

CDC14A p.Arg376Ter (c.1126C>T) is ultra-rare (popmax 0.0172%, mid) (gnomAD).

CDC14A p.Arg376Ter

c.1126C>T · rs876661408 · VCV235145

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, mid)

Conditions

autosomal recessive nonsyndromic hearing loss 32

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	predicted	premature termination codon in exon 11 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.9, phastCons 0.93
Overall
CADD	35.0	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 0.0172% Middle Eastern · 1/5,816 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000555% 8/1,442,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0172%	5,816
South Asian	0.00115%	86,906
European (non-Finnish)	0.000511%	195,513

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: CDC14A
Protein: p.Arg376Ter
Coding: c.1126C>T
MANE Select: NM_003672
dbSNP: rs876661408
Type: single nucleotide variant
Location: chr1:100484440 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.77
Residue 376: a UniProt-annotated variant site (in dfnb32)

Full CDC14A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 32 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ear malformation

Similar variants

CDC14A p.Arg376Gln Uncertain significance ★★ ⚠ same residue
CDC14A p.Arg376= Likely benign ★ same residue
CDC14A p.Arg312Gln Pathogenic/Likely pathogenic ★★ same condition
CDC14A p.Arg312Gly Pathogenic/Likely pathogenic ★★ same condition
CDC14A p.Arg339Ter Pathogenic ★★ same condition
CDC14A p.Arg345Ter Pathogenic/Likely pathogenic ★★ same condition
CDC14A p.Arg582His Uncertain significance ★★ ⚠ same condition
CDC14A c.1251-139A>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/cdc14a-p-arg376ter (accessed [today's date]).

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