Is CDK4 p.Ala248Asp (c.743C>A) pathogenic?

CDK4 p.Ala248Asp (c.743C>A) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-07). AlphaMissense: ambiguous (0.4775); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Ala248Asp (c.743C>A)?

CDK4 p.Ala248Asp (c.743C>A) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Ala248Asp (c.743C>A) in the general population?

CDK4 p.Ala248Asp (c.743C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CDK4 p.Ala248Asp (c.743C>A)?

AlphaMissense predicts ambiguous (score 0.4775) — an in-silico prediction, not a clinical call.

CDK4 p.Ala248Asp

c.743C>A · rs1595108770 · VCV1010775

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4775	ambiguous
REVEL	0.09	moderately benign-leaning
SaProt	LLR -10.00	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	24.7	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 8.48e-05% European (non-Finnish) · 1/1,179,940 alleles

Overall 6.84e-05% 1/1,461,758 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.Ala248Asp
Coding: c.743C>A
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs1595108770
Type: single nucleotide variant
Location: chr12:57749258 (GRCh38)

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

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-ala248asp (accessed [today's date]).

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