Is CDKN2A p.Met1Lys (c.2T>A) pathogenic?

CDKN2A p.Met1Lys (c.2T>A) is classified Likely pathogenic in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-21). Very rare (popmax 8.49e-05%, nfe); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Met1Lys (c.2T>A)?

CDKN2A p.Met1Lys (c.2T>A) is associated with melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Met1Lys (c.2T>A) in the general population?

CDKN2A p.Met1Lys (c.2T>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

CDKN2A p.Met1Lys

Q: How is Familial atypical multiple mole melanoma syndrome inherited?

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

c.2T>A · VCV4856720

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.608	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.3, phastCons 1
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,836 alleles

Overall 6.88e-05% 1/1,454,182 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.Met1Lys
Coding: c.2T>A
MANE Select: NM_000077 · reported on NM_058195
Type: single nucleotide variant
Location: chr9:21994330 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 1: a modified residue (n-acetylmethionine); the 'interaction with cdk5rap3 and mdm2' region

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

Disease context

melanoma-pancreatic cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Met1Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Met1Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Met1Arg Uncertain significance ★★ same residue
CDKN2A p.Met1Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Met1Leu Uncertain significance ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A 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-met1lys (accessed [today's date]).

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