Is CDKN2A p.Ala21Ser (c.61G>T) pathogenic?

CDKN2A p.Ala21Ser (c.61G>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-24). AlphaMissense: likely benign (0.1823); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala21Ser (c.61G>T)?

CDKN2A p.Ala21Ser (c.61G>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Ala21Ser (c.61G>T) in the general population?

CDKN2A p.Ala21Ser (c.61G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Ala21Ser (c.61G>T)?

AlphaMissense predicts likely benign (score 0.1823) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala21Ser

c.61G>T · rs1064793082 · VCV928884

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1823 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1823	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -6.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: CDKN2A
Protein: p.Ala21Ser
Coding: c.61G>T
MANE Select: NM_000077
dbSNP: rs1064793082
Type: single nucleotide variant
Location: chr9:21974767 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 21: an α-helix; the 'interaction with cdk5rap3 and mdm2' region

Full CDKN2A 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

CDKN2A p.Ala21Asp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala21Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala21Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg21Lys Uncertain significance ★★ same residue
CDKN2A p.Arg21Trp Uncertain significance ★ same residue
CDKN2A p.Ala21_Arg22insAlaAla Uncertain significance ★ same residue
CDKN2A p.Arg21Glu Uncertain significance ★ same residue
CDKN2A p.Arg21= Benign ★ same residue

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/cdkn2a-p-ala21ser (accessed [today's date]).

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