Is CDC14A p.Pro125Arg (c.374C>G) pathogenic?

CDC14A p.Pro125Arg (c.374C>G) is classified Uncertain significance in CDC14A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.4738); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CDC14A p.Pro125Arg (c.374C>G)?

CDC14A p.Pro125Arg (c.374C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CDC14A p.Pro125Arg (c.374C>G) in the general population?

CDC14A p.Pro125Arg (c.374C>G) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about CDC14A p.Pro125Arg (c.374C>G)?

AlphaMissense predicts ambiguous (score 0.4738) — an in-silico prediction, not a clinical call.

CDC14A p.Pro125Arg

c.374C>G · rs200941208 · VCV666801

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4738	ambiguous
REVEL	0.114	moderately benign-leaning
SaProt	LLR -11.54	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
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	21.1	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 0.0223% East Asian · 10/44,876 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00329% 53/1,613,212 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,488
African / African-American	0.012%	8,330
South Asian	0.00549%	18,213
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.00229%	43,676

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.Pro125Arg
Coding: c.374C>G
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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDC14A p.Pro125His Uncertain significance ★★ ⚠ same residue
CDC14A p.Pro125Leu Uncertain significance ★★ ⚠ same residue
CDC14A p.Pro125Ala Uncertain significance ★ ⚠ same residue
CDC14A p.Ala211Gly Uncertain significance ★★ ⚠ same condition
CDC14A p.Ala482Thr Uncertain significance ★★ ⚠ same condition
CDC14A p.Arg261Gln Uncertain significance ★★ ⚠ same condition
CDC14A p.Arg376Gln Uncertain significance ★★ ⚠ same condition
CDC14A p.Cys12Tyr Uncertain significance ★★ ⚠ 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-pro125arg (accessed [today's date]).

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