Is CDK4 p.Glu115Ala (c.344A>C) pathogenic?

CDK4 p.Glu115Ala (c.344A>C) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-23). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Glu115Ala (c.344A>C)?

CDK4 p.Glu115Ala (c.344A>C) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Glu115Ala (c.344A>C) in the general population?

CDK4 p.Glu115Ala (c.344A>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDK4 p.Glu115Ala (c.344A>C)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

CDK4 p.Glu115Ala

c.344A>C · rs1955233133 · VCV846017

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -3.58	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	18.98	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 0.00223% East Asian · 1/44,876 alleles

Overall 0.000137% 2/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
European (non-Finnish)	8.47e-05%	1,180,025

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: CDK4
Protein: p.Glu115Ala
Coding: c.344A>C
MANE Select: NM_000075
dbSNP: rs1955233133
Type: single nucleotide variant
Location: chr12:57751217 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 115: the protein kinase domain; an α-helix

Full CDK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial melanoma

Similar variants

CDK4 p.Glu115Gln Uncertain significance ★★ ⚠ same residue
CDK4 p.Glu115Lys Uncertain significance ★★ ⚠ same residue
CDK4 p.Glu115Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
CDK4 p.Glu115Gly Uncertain significance ★ ⚠ same residue
CDK4 p.Glu115Ter Uncertain significance ★ same residue
CDK4 p.Arg24Cys Pathogenic ★★ same condition
CDK4 p.Arg24His Pathogenic ★★ same condition
CDK4 c.354+3G>C 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/cdk4-p-glu115ala (accessed [today's date]).

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