Is CDKN2A p.Gly23Asp (c.68G>A) pathogenic?

CDKN2A p.Gly23Asp (c.68G>A) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.8537); Very rare (popmax 0.00017%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Gly23Asp (c.68G>A)?

CDKN2A p.Gly23Asp (c.68G>A) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Gly23Asp (c.68G>A) in the general population?

CDKN2A p.Gly23Asp (c.68G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Gly23Asp (c.68G>A)?

AlphaMissense predicts likely pathogenic (score 0.8537) — an in-silico prediction, not a clinical call.

CDKN2A p.Gly23Asp

c.68G>A · rs1064794292 · VCV420108

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8537	likely pathogenic ✓ concordant with ClinVar
REVEL	0.754	pathogenic-leaning
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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	25.1	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,424 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,457,454 alleles · very rare

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: CDKN2A
Protein: p.Gly23Asp
Coding: c.68G>A
MANE Select: NM_000077
dbSNP: rs1064794292
Type: single nucleotide variant
Location: chr9:21974760 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Gly23Arg Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly23Cys Likely pathogenic ★★ same residue
CDKN2A p.Gly23Ser 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-gly23asp (accessed [today's date]).

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