Is CDK4 p.Thr149= (c.447A>G) pathogenic?

CDK4 p.Thr149= (c.447A>G) is classified Benign in CDK4 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.24%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Thr149= (c.447A>G)?

CDK4 p.Thr149= (c.447A>G) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 3, familial melanoma (ClinVar).

How common is CDK4 p.Thr149= (c.447A>G) in the general population?

CDK4 p.Thr149= (c.447A>G) is low-frequency (popmax 2.24%, afr) (gnomAD).

CDK4 p.Thr149=

c.447A>G · rs2069501 · VCV184152

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.24%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -1.1, phastCons 0.003
Overall
CADD	5.862	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.24% African / African-American · 1,682/75,002 alleles

Filtering AF 2.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.12%

Overall 0.121% 1,949/1,614,128 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.24%	45
Admixed American	0.175%	572
Remaining individualsnot grpmax-eligible	0.15%	665
Middle Eastern	0.132%	758
South Asian	0.011%	9,107
European (non-Finnish)	0.00424%	23,600

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.Thr149=
Coding: c.447A>G
MANE Select: NM_000075
dbSNP: rs2069501
Type: single nucleotide variant
Location: chr12:57750998 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 149: the protein kinase domain

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: melanoma, cutaneous malignant, susceptibility to, 3 familial melanoma

Similar variants

CDK4 p.Thr149Ala Uncertain significance ★★ same residue
CDK4 p.Thr149Ser 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
CDK4 c.355-4C>G Uncertain significance ★★ same condition
CDK4 c.632+5G>A 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-thr149 (accessed [today's date]).

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