Is CDC14A p.Leu516Phe (c.1546C>T) pathogenic?

CDC14A p.Leu516Phe (c.1546C>T) is classified Uncertain significance in CDC14A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0534); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with CDC14A p.Leu516Phe (c.1546C>T)?

CDC14A p.Leu516Phe (c.1546C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDC14A p.Leu516Phe (c.1546C>T) in the general population?

CDC14A p.Leu516Phe (c.1546C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CDC14A p.Leu516Phe (c.1546C>T)?

AlphaMissense predicts likely benign (score 0.0534) — an in-silico prediction, not a clinical call.

CDC14A p.Leu516Phe

c.1546C>T · rs376296207 · VCV2300226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0534	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP 0.55, phastCons 0.74
Regional constraint	o/e 0.91	unconstrained · MANE · 165 kb · p 0.011 · regional, not allelic
Overall
CADD	14.9	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 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,064 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
East Asian	0.00223%	44,898

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.Leu516Phe
Coding: c.1546C>T
MANE Select: NM_003672
dbSNP: rs376296207
Type: single nucleotide variant
Location: chr1:100499053 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.77
Residue 516: 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.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
CDC14A p.Gly423Glu 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-leu516phe (accessed [today's date]).

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