Is CDC14A p.Ala458fs (c.1371_1386del) pathogenic?

CDC14A p.Ala458fs (c.13711386del) is classified Uncertain significance in CDC14A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). Ultra-rare (popmax 0.01%, amr).

How common is CDC14A p.Ala458fs (c.1371_1386del) in the general population?

CDC14A p.Ala458fs (c.1371_1386del) is ultra-rare (popmax 0.01%, amr) (gnomAD).

CDC14A p.Ala458fs

c.1371_1386del · rs765303977 · VCV2131961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP 0.33, phastCons 0.99
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 0.01% Admixed American · 6/59,990 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.0018% 29/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
European (non-Finnish)	0.00195%	51,304

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.Ala458fs
Coding: c.1371_1386del
MANE Select: NM_003672
dbSNP: rs765303977
Type: Deletion
Location: chr1:100498153 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.77
Residue 458: a UniProt-annotated variant site (in dfnb32)

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

Similar variants

CDC14A p.Ala458Thr Uncertain significance ★ ⚠ same residue
CDC14A p.Ala451fs Pathogenic ★ same type
CDC14A p.Tyr126fs Pathogenic ★ same type
CDC14A c.1299-2del Uncertain significance ★ same type
CDC14A c.1755+108del Uncertain significance ★ same type
CDC14A p.Ile183_Val184del Uncertain significance ★ same type
CDC14A p.Pro205del Uncertain significance ★ same type
CDC14A p.Ser575fs Uncertain significance ★ same type

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-ala458fs (accessed [today's date]).

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