Is CDKN2A p.Val43Leu (c.127G>C) pathogenic?

CDKN2A p.Val43Leu (c.127G>C) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-22). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Val43Leu (c.127G>C)?

CDKN2A p.Val43Leu (c.127G>C) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Val43Leu (c.127G>C) in the general population?

CDKN2A p.Val43Leu (c.127G>C) is absent from gnomAD v4.1 (gnomAD).

CDKN2A p.Val43Leu

c.127G>C · rs1820529552 · VCV959875

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.127	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.3, phastCons 0.007
Overall
CADD	18.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2A
Protein: p.Val43Leu
Coding: c.127G>C
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1820529552
Type: single nucleotide variant
Location: chr9:21994205 (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

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

Also linked: familial melanoma

Similar variants

CDKN2A p.Ser43Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ser43Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ser43= Benign/Likely benign ★★ same residue
CDKN2A p.Ser43Asn Uncertain significance ★ ⚠ same residue
CDKN2A p.Val43Ala Uncertain significance ★ same residue
CDKN2A p.Ser43_Tyr44insTer Pathogenic ★★ same residue
CDKN2A p.Ser43Ter Pathogenic ★★ same residue
CDKN2A p.Val43fs Pathogenic ★ 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-val43leu (accessed [today's date]).

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