Is CDC14A p.Pro125Leu (c.374C>T) pathogenic?

CDC14A p.Pro125Leu (c.374C>T) is classified Uncertain significance in CDC14A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.2186); Ultra-rare (popmax 0.02%, afr).

How common is CDC14A p.Pro125Leu (c.374C>T) in the general population?

CDC14A p.Pro125Leu (c.374C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about CDC14A p.Pro125Leu (c.374C>T)?

AlphaMissense predicts likely benign (score 0.2186) — an in-silico prediction, not a clinical call.

CDC14A p.Pro125Leu

c.374C>T · rs200941208 · VCV2571790

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2186	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -11.40	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 165 kb · p 0.011 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/74,848 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0099%

Overall 0.00508% 82/1,613,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,930
African / African-Americangrpmax	0.02%	4,990
European (non-Finnish)	0.00475%	21,058
Remaining individualsnot grpmax-eligible	0.0032%	31,225
South Asian	0.0022%	45,535
Admixed American	0.00167%	59,990

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: CDC14A
Protein: p.Pro125Leu
Coding: c.374C>T
MANE Select: NM_003672
dbSNP: rs200941208
Type: single nucleotide variant
Location: chr1:100424286 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.77
Residue 125: the 'a' region

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

Similar variants

CDC14A p.Pro125Arg Uncertain significance ★★ ⚠ same residue
CDC14A p.Pro125His Uncertain significance ★★ ⚠ same residue
CDC14A p.Pro125Ala Uncertain significance ★ ⚠ same residue
CDC14A p.Arg261Ter Pathogenic ★★ same type
CDC14A p.Arg312Gln Pathogenic/Likely pathogenic ★★ same type
CDC14A p.Arg312Gly Pathogenic/Likely pathogenic ★★ same type
CDC14A p.Arg339Ter Pathogenic ★★ same type
CDC14A p.Arg345Ter Pathogenic/Likely pathogenic ★★ 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-pro125leu (accessed [today's date]).

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