Is CDKN2A p.Leu32Val (c.94C>G) pathogenic?

CDKN2A p.Leu32Val (c.94C>G) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.3013); Very rare (popmax 0.005%, amr); Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Leu32Val (c.94C>G)?

CDKN2A p.Leu32Val (c.94C>G) is associated with melanoma and neural system tumor syndrome, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Leu32Val (c.94C>G) in the general population?

CDKN2A p.Leu32Val (c.94C>G) is very rare (popmax 0.005%, amr) (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.Leu32Val (c.94C>G)?

AlphaMissense predicts likely benign (score 0.3013) — an in-silico prediction, not a clinical call.

CDKN2A p.Leu32Val

c.94C>G · rs745827714 · VCV532278

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3013 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.3013	likely benign
REVEL	0.673	pathogenic-leaning
SaProt	LLR -10.20	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.6	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 0.005% Admixed American · 3/59,982 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,460,394 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.Leu32Val
Coding: c.94C>G
MANE Select: NM_000077
dbSNP: rs745827714
Type: single nucleotide variant
Location: chr9:21974734 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 32: an α-helix; a UniProt-annotated variant site (in cmm2); 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.Leu32Pro Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly32Glu Uncertain significance ★★ same residue
CDKN2A p.Gly32= Benign/Likely benign ★★ same residue
CDKN2A p.Leu32= Benign/Likely benign ★★ same residue
CDKN2A p.Gly32Ala Uncertain significance ★ same residue
CDKN2A p.Gly32Arg Uncertain significance ★ same residue
CDKN2A p.Leu32_Leu37del Pathogenic ★★ same residue
CDKN2A c.150+1G>A 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-leu32val (accessed [today's date]).

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