Is CDKN2A p.Glu2Gln (c.4G>C) pathogenic?

CDKN2A p.Glu2Gln (c.4G>C) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0927); Very rare (popmax 0.00135%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Glu2Gln (c.4G>C)?

CDKN2A p.Glu2Gln (c.4G>C) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Glu2Gln (c.4G>C) in the general population?

CDKN2A p.Glu2Gln (c.4G>C) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about CDKN2A p.Glu2Gln (c.4G>C)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

CDKN2A p.Glu2Gln

c.4G>C · rs1060501273 · VCV406722

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.4, phastCons 0.007
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	15.08	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 0.00135% African / African-American · 1/74,332 alleles

Overall 0.000126% 2/1,592,086 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,332
European (non-Finnish)	8.52e-05%	1,173,540

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.Glu2Gln
Coding: c.4G>C
MANE Select: NM_000077
dbSNP: rs1060501273
Type: single nucleotide variant
Location: chr9:21974824 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 2: 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.Val2Met Uncertain significance ★★ same residue
CDKN2A p.Glu2Asp Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Val2Glu Uncertain significance ★ same residue
CDKN2A p.Val2Leu Uncertain significance ★ same residue
CDKN2A p.Glu2_Pro3insArgAlaAlaGlySerSerMetGlu Uncertain significance ★★ same residue
CDKN2A p.Val2= 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-glu2gln (accessed [today's date]).

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