Is CDK4 p.Pro194His (c.581C>A) pathogenic?

CDK4 p.Pro194His (c.581C>A) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-16). AlphaMissense: likely pathogenic (0.884); Absent from gnomAD v4.1; Associated with melanoma, cutaneous malignant, susceptibility to, 3.

What condition is associated with CDK4 p.Pro194His (c.581C>A)?

CDK4 p.Pro194His (c.581C>A) is associated with melanoma, cutaneous malignant, susceptibility to, 3, familial melanoma (ClinVar).

How common is CDK4 p.Pro194His (c.581C>A) in the general population?

CDK4 p.Pro194His (c.581C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDK4 p.Pro194His (c.581C>A)?

AlphaMissense predicts likely pathogenic (score 0.884) — an in-silico prediction, not a clinical call.

CDK4 p.Pro194His

c.581C>A · rs1198423952 · VCV845643

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.884 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma, cutaneous malignant, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.884	likely pathogenic
REVEL	0.45	indeterminate
SaProt	LLR -14.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDK4
Protein: p.Pro194His
Coding: c.581C>A
MANE Select: NM_000075
dbSNP: rs1198423952
Type: single nucleotide variant
Location: chr12:57750707 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 194: the protein kinase domain

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

Disease context

melanoma, cutaneous malignant, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial melanoma

Similar variants

CDK4 p.Pro194Leu Uncertain significance ★★ ⚠ same residue
CDK4 p.Pro194Ser Uncertain significance ★★ ⚠ same residue
CDK4 p.Pro194Ala Uncertain significance ★ ⚠ same residue
CDK4 p.Pro194Thr 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
CDK4 c.354+5G>T 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-pro194his (accessed [today's date]).

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