Is CDKN2A p.Ala40Ser (c.118G>T) pathogenic?

CDKN2A p.Ala40Ser (c.118G>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.1333); Very rare (popmax 0.000593%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Ala40Ser (c.118G>T)?

CDKN2A p.Ala40Ser (c.118G>T) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ala40Ser (c.118G>T) in the general population?

CDKN2A p.Ala40Ser (c.118G>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Familial melanoma inherited?

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

What do computational predictors say about CDKN2A p.Ala40Ser (c.118G>T)?

AlphaMissense predicts likely benign (score 0.1333) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala40Ser

c.118G>T · rs1554656295 · VCV491563

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.1333	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.3	GERP 1.2, phastCons 0.001
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,820 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,459,870 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.Ala40Ser
Coding: c.118G>T
MANE Select: NM_000077
dbSNP: rs1554656295
Type: single nucleotide variant
Location: chr9:21974710 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 40: an α-helix; the 'interaction with cdk5rap3 and mdm2' region

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

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Ala40= Benign/Likely benign ★★ same residue
CDKN2A p.Ala40Pro Uncertain significance ★ same residue
CDKN2A p.Ala40Thr Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala40Val Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro40= Likely benign ★ same residue
CDKN2A p.Pro40_Ala41delinsThr 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-ala40ser (accessed [today's date]).

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