Is CDKN2A p.Val115Glu (c.344T>A) pathogenic?

CDKN2A p.Val115Glu (c.344T>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-06). AlphaMissense: likely benign (0.3085); Ultra-rare (popmax 0.0223%, eas); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Val115Glu (c.344T>A)?

CDKN2A p.Val115Glu (c.344T>A) is associated with melanoma-pancreatic cancer syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Val115Glu (c.344T>A) in the general population?

CDKN2A p.Val115Glu (c.344T>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about CDKN2A p.Val115Glu (c.344T>A)?

AlphaMissense predicts likely benign (score 0.3085) — an in-silico prediction, not a clinical call.

CDKN2A p.Val115Glu

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.344T>A · rs750655995 · VCV246437

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.3085	likely benign
REVEL	0.526	indeterminate
SaProt	LLR -10.37	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.3	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 0.0223% East Asian · 10/44,882 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000622% 10/1,607,670 alleles · ultra-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.Val115Glu
Coding: c.344T>A
MANE Select: NM_000077
dbSNP: rs750655995
Type: single nucleotide variant
Location: chr9:21971015 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 115: an α-helix; 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: melanoma, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome hereditary neoplastic syndrome familial melanoma

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Val115Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val115Leu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val115Met Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val115= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Val115fs 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-val115glu (accessed [today's date]).

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