Is CDKN2A p.Leu91= (c.273G>A) pathogenic?

CDKN2A p.Leu91= (c.273G>A) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-26). Rare (popmax 0.119%, afr); Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu91= (c.273G>A)?

CDKN2A p.Leu91= (c.273G>A) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu91= (c.273G>A) in the general population?

CDKN2A p.Leu91= (c.273G>A) is rare (popmax 0.119%, afr) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Leu91=

c.273G>A · rs4987127 · VCV133882

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.119%, afr)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.68	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2, phastCons 1
Overall
CADD	13.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.119% African / African-American · 89/75,030 alleles

Filtering AF 0.0987% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0913%

Overall 0.00729% 117/1,605,320 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.119%	843
Middle Eastern	0.0882%	1,133
Admixed American	0.0117%	8,568
Remaining individualsnot grpmax-eligible	0.0112%	8,911
South Asian	0.0011%	90,986
European (non-Finnish)	0.000678%	147,445

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.Leu91=
Coding: c.273G>A
MANE Select: NM_000077
dbSNP: rs4987127
Type: single nucleotide variant
Location: chr9:21971086 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 91: an α-helix; the 'disordered' 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

Also linked: melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Leu91Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu91Met Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu91Lys Uncertain significance ★ 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
CDKN2A c.151-1G>C Pathogenic ★★ same condition
CDKN2A c.151-1G>T Pathogenic/Likely 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-leu91 (accessed [today's date]).

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