Is CDKN2A p.Pro81Ser (c.241C>T) pathogenic?

CDKN2A p.Pro81Ser (c.241C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-13). AlphaMissense: likely pathogenic (0.8599); Very rare (popmax 8.48e-05%, nfe); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Pro81Ser (c.241C>T)?

CDKN2A p.Pro81Ser (c.241C>T) is associated with melanoma-pancreatic cancer syndrome, familial pancreatic carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Pro81Ser (c.241C>T) in the general population?

CDKN2A p.Pro81Ser (c.241C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Pro81Ser (c.241C>T)?

AlphaMissense predicts likely pathogenic (score 0.8599) — an in-silico prediction, not a clinical call.

CDKN2A p.Pro81Ser

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.241C>T · rs1334828764 · VCV664812

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8599 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.8599	likely pathogenic
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -11.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.25	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,179,556 alleles

Overall 0.000657% 1/152,230 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.Pro81Ser
Coding: c.241C>T
MANE Select: NM_000077
dbSNP: rs1334828764
Type: single nucleotide variant
Location: chr9:21971118 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 81: an α-helix; a UniProt-annotated variant site (in some patients with melanoma; impairs the function); a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); the 'disordered' 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 pancreatic carcinoma hereditary neoplastic syndrome Li-Fraumeni syndrome familial melanoma

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Pro81Leu Likely pathogenic ★★ same residue
CDKN2A p.Pro81= Uncertain significance ★ same residue
CDKN2A p.Pro81Ala Uncertain significance ★ same residue
CDKN2A p.Pro81Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro81Thr Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro81fs Pathogenic ★★ 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-pro81ser (accessed [today's date]).

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