Is CDC14A p.Arg409Cys (c.1225C>T) pathogenic?

CDC14A p.Arg409Cys (c.1225C>T) is classified Uncertain significance in CDC14A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely benign (0.1294); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with CDC14A p.Arg409Cys (c.1225C>T)?

CDC14A p.Arg409Cys (c.1225C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDC14A p.Arg409Cys (c.1225C>T) in the general population?

CDC14A p.Arg409Cys (c.1225C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDC14A p.Arg409Cys (c.1225C>T)?

AlphaMissense predicts likely benign (score 0.1294) — an in-silico prediction, not a clinical call.

CDC14A p.Arg409Cys

c.1225C>T · VCV3998436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1294	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.95 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 165 kb · p 0.011 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,976 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000904%

Overall 0.00149% 24/1,608,282 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,988
South Asian	0.0022%	45,460
European (non-Finnish)	0.0017%	58,744

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.Arg409Cys
Coding: c.1225C>T
MANE Select: NM_003672
Type: single nucleotide variant
Location: chr1:100494905 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.77
Residue 409: a UniProt-annotated variant site (in dfnb32); the 'disordered' 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.Arg409Leu 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
CDC14A p.Glu271Lys Uncertain significance ★★ ⚠ same condition
CDC14A p.Gly283Ala 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-arg409cys (accessed [today's date]).

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