Is CDKN2A p.Gly23Ser (c.67G>A) pathogenic?

CDKN2A p.Gly23Ser (c.67G>A) is classified Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.6877); Absent from gnomAD v4.1; Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Gly23Ser (c.67G>A)?

CDKN2A p.Gly23Ser (c.67G>A) is associated with melanoma and neural system tumor syndrome, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Gly23Ser (c.67G>A) in the general population?

CDKN2A p.Gly23Ser (c.67G>A) is absent from gnomAD v4.1 (gnomAD).

How is Melanoma and neural system tumor syndrome inherited?

Typically Autosomal dominant, Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN2A p.Gly23Ser (c.67G>A)?

AlphaMissense predicts likely pathogenic (score 0.6877) — an in-silico prediction, not a clinical call.

CDKN2A p.Gly23Ser

c.67G>A · rs1131691186 · VCV429108

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6877 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.6877	likely pathogenic ✓ concordant with ClinVar
REVEL	0.505	indeterminate
SaProt	LLR -11.23	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 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

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.Gly23Ser
Coding: c.67G>A
MANE Select: NM_000077
dbSNP: rs1131691186
Type: single nucleotide variant
Location: chr9:21974761 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 23: a UniProt-annotated variant site (in a pancreas tumor and a melanoma; loss of cdk4 binding); the 'interaction with cdk5rap3 and mdm2' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

melanoma and neural system tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial melanoma

For Melanoma and neural system tumor syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult, Elderly

Similar variants

CDKN2A p.Gly23Arg Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly23Asp Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly23Cys Likely pathogenic ★★ same residue
CDKN2A p.Phe23Leu Uncertain significance ★★ same residue
CDKN2A p.Phe23= Benign/Likely benign ★★ same residue
CDKN2A p.Gly23= Likely benign ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ 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/cdkn2a-p-gly23ser (accessed [today's date]).

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