Is CDKN2A p.Val46Met (c.136G>A) pathogenic?

CDKN2A p.Val46Met (c.136G>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-19). Very rare (popmax 0.00267%, afr); Associated with melanoma, cutaneous malignant, susceptibility to, 2.

What condition is associated with CDKN2A p.Val46Met (c.136G>A)?

CDKN2A p.Val46Met (c.136G>A) is associated with melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Val46Met (c.136G>A) in the general population?

CDKN2A p.Val46Met (c.136G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

CDKN2A p.Val46Met

c.136G>A · rs786203467 · VCV187095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

melanoma, cutaneous malignant, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.481	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.49	GERP -1.6
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,942 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000187% 3/1,606,346 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,471
European (non-Finnish)	8.48e-05%	1,179,874

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.Val46Met
Coding: c.136G>A
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs786203467
Type: single nucleotide variant
Location: chr9:21994196 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 46: the 'interaction with cdk5rap3 and mdm2' region

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

Disease context

melanoma, cutaneous malignant, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome familial melanoma

Similar variants

CDKN2A p.Arg46Gln Uncertain significance ★★ same residue
CDKN2A p.Arg46Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val46= Benign/Likely benign ★★ same residue
CDKN2A p.Arg46= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Arg46Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Val46Ala Uncertain significance ★ same residue
CDKN2A p.Val46Gly Uncertain significance ★ same residue
CDKN2A p.Val46Leu Uncertain significance ★ 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-val46met (accessed [today's date]).

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