Is CDKN2A p.Pro114Ser (c.340C>T) pathogenic?

CDKN2A p.Pro114Ser (c.340C>T) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-26). AlphaMissense: likely pathogenic (0.8619); Very rare (popmax 8.48e-05%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Pro114Ser (c.340C>T)?

CDKN2A p.Pro114Ser (c.340C>T) is associated with familial melanoma (ClinVar).

How common is CDKN2A p.Pro114Ser (c.340C>T) in the general population?

CDKN2A p.Pro114Ser (c.340C>T) is very rare (popmax 8.48e-05%, 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.Pro114Ser (c.340C>T)?

AlphaMissense predicts likely pathogenic (score 0.8619) — an in-silico prediction, not a clinical call.

CDKN2A p.Pro114Ser

c.340C>T · rs104894104 · VCV1405931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8619 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.8619	likely pathogenic
REVEL	0.759	pathogenic-leaning
SaProt	LLR -13.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,714 alleles

Overall 6.22e-05% 1/1,607,566 alleles · very rare exomes 0/1,455,220 · genomes 1/152,346 · joint denominator

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.Pro114Ser
Coding: c.340C>T
MANE Select: NM_000077
dbSNP: rs104894104
Type: single nucleotide variant
Location: chr9:21971019 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 114: an α-helix; a UniProt-annotated variant site (in non-small cell lung carcinoma); a UniProt-annotated variant site (found in some patients with melanoma; loss of cdk4 binding); the 'disordered' 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

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Pro114= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Pro114Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro114Thr Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro114fs Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Pro114Arg Likely pathogenic ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A Pathogenic ★★ same condition
CDKN2A c.151-1G>C 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-pro114ser (accessed [today's date]).

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