Is CDKN2A p.Val43fs (c.126_127insCA) pathogenic?

CDKN2A p.Val43fs (c.126127insCA) is classified Pathogenic in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). Absent from gnomAD; Associated with familial melanoma.

What condition is associated with CDKN2A p.Val43fs (c.126_127insCA)?

CDKN2A p.Val43fs (c.126_127insCA) is associated with familial melanoma (ClinVar).

How common is CDKN2A p.Val43fs (c.126_127insCA) in the general population?

CDKN2A p.Val43fs (c.126_127insCA) is absent from gnomAD (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

CDKN2A p.Val43fs

c.126_127insCA · rs2131148302 · VCV1072356

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 1.3, phastCons 0.007

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKN2A
Protein: p.Val43fs
Coding: c.126_127insCA
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs2131148302
Type: Insertion
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

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.Ser43_Tyr44insTer Pathogenic ★★ same residue
CDKN2A p.Ser43Ter Pathogenic ★★ same residue
CDKN2A p.Ser43Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ser43Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val43Leu 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

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-val43fs (accessed [today's date]).

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