Is CDKN2A p.Met1Ile (c.3G>C) pathogenic?

CDKN2A p.Met1Ile (c.3G>C) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-12). Absent from gnomAD v4.1; Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Met1Ile (c.3G>C)?

CDKN2A p.Met1Ile (c.3G>C) is associated with melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Met1Ile (c.3G>C) in the general population?

CDKN2A p.Met1Ile (c.3G>C) is absent from gnomAD v4.1 (gnomAD).

CDKN2A p.Met1Ile

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.3G>C · rs1820538211 · VCV1018474

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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	0.438	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.61, phastCons 1
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2A
Protein: p.Met1Ile
Coding: c.3G>C
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1820538211
Type: single nucleotide variant
Location: chr9:21994329 (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

Also linked: familial melanoma

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Met1Arg Uncertain significance ★★ same residue
CDKN2A p.Met1Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Met1Lys Likely pathogenic ★ same residue
CDKN2A p.Met1Leu Uncertain significance ★ same residue
CDKN2A p.Met1Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Met1fs Uncertain significance ★ 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-met1ile (accessed [today's date]).

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