Is CDK4 p.Phe227Ser (c.680T>C) pathogenic?

CDK4 p.Phe227Ser (c.680T>C) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-17). AlphaMissense: likely pathogenic (0.9441); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Phe227Ser (c.680T>C)?

CDK4 p.Phe227Ser (c.680T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Phe227Ser (c.680T>C) in the general population?

CDK4 p.Phe227Ser (c.680T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDK4 p.Phe227Ser (c.680T>C)?

AlphaMissense predicts likely pathogenic (score 0.9441) — an in-silico prediction, not a clinical call.

CDK4 p.Phe227Ser

c.680T>C · rs1481057693 · VCV993216

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9441 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9441	likely pathogenic
REVEL	0.535	indeterminate
SaProt	LLR -14.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.1	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	29.0	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.Phe227Ser
Coding: c.680T>C
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs1481057693
Type: single nucleotide variant
Location: chr12:57749457 (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

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-phe227ser (accessed [today's date]).

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