Is CDKN2A p.Pro114= (c.342C>G) pathogenic?

CDKN2A p.Pro114= (c.342C>G) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-23). Very rare (popmax 0.00834%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro114= (c.342C>G)?

CDKN2A p.Pro114= (c.342C>G) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro114= (c.342C>G) in the general population?

CDKN2A p.Pro114= (c.342C>G) is very rare (popmax 0.00834%, amr) (gnomAD).

CDKN2A p.Pro114=

c.342C>G · rs878853648 · VCV236986

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.331	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.047	GERP 0.18, phastCons 0.28
Overall
CADD	11.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,980 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00199% 32/1,607,770 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,996
Remaining individualsnot grpmax-eligible	0.00321%	31,181
African / African-American	0.00267%	37,522
European (non-Finnish)	0.00195%	51,293

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.Pro114=
Coding: c.342C>G
MANE Select: NM_000077
dbSNP: rs878853648
Type: single nucleotide variant
Location: chr9:21971017 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial melanoma

Similar variants

CDKN2A p.Pro114Arg Likely pathogenic ★ same residue
CDKN2A p.Pro114Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro114Ser Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro114Thr Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro114fs Pathogenic/Likely pathogenic ★★ 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-pro114 (accessed [today's date]).

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