Is CDKN2A p.Val43= (c.129G>A) pathogenic?

CDKN2A p.Val43= (c.129G>A) is classified Benign in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). Very rare (popmax 0.0011%, sas); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Val43= (c.129G>A)?

CDKN2A p.Val43= (c.129G>A) is associated with melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Val43= (c.129G>A) in the general population?

CDKN2A p.Val43= (c.129G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

CDKN2A p.Val43=

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.129G>A · VCV4294109

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.6, phastCons 0.85
Overall
CADD	12.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,050 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,606,716 alleles · very rare exomes 3/1,454,414 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,050
European (non-Finnish)	0.00017%	589,904

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.Val43=
Coding: c.129G>A
MANE Select: NM_000077 · reported on NM_058195
Type: single nucleotide variant
Location: chr9:21994203 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 43: a β-strand; the 'interaction with cdk5rap3 and mdm2' 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

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Ser43Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ser43= Benign/Likely benign ★★ same residue
CDKN2A p.Ser43_Tyr44insTer Pathogenic ★★ same residue
CDKN2A p.Ser43Ter Pathogenic ★★ same residue
CDKN2A p.Ser43Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val43Leu Uncertain significance ★★ same residue
CDKN2A p.Ser43Asn Uncertain significance ★ ⚠ same residue
CDKN2A p.Val43Ala Uncertain significance ★ same residue

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-val43 (accessed [today's date]).

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