Is CDK4 p.Glu115Asp (c.345A>C) pathogenic?

CDK4 p.Glu115Asp (c.345A>C) is classified Conflicting classifications of pathogenicity in CDK4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-16). AlphaMissense: likely benign (0.0726); Very rare (popmax 0.00333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Glu115Asp (c.345A>C)?

CDK4 p.Glu115Asp (c.345A>C) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Glu115Asp (c.345A>C) in the general population?

CDK4 p.Glu115Asp (c.345A>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDK4 p.Glu115Asp (c.345A>C)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

CDK4 p.Glu115Asp

c.345A>C · rs769378936 · VCV954054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -5.98	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 -0.032	GERP -1.6, phastCons 0.75
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	7.052	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 0.00333% Admixed American · 2/60,030 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

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

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.Glu115Asp
Coding: c.345A>C
MANE Select: NM_000075
dbSNP: rs769378936
Type: single nucleotide variant
Location: chr12:57751216 (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.Glu115Ala Uncertain significance ★★ ⚠ same residue
CDK4 p.Glu115Gln Uncertain significance ★★ ⚠ same residue
CDK4 p.Glu115Lys Uncertain significance ★★ ⚠ 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-glu115asp (accessed [today's date]).

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