Is CDKN2A p.Leu60Phe (c.178C>T) pathogenic?

CDKN2A p.Leu60Phe (c.178C>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-22). Ultra-rare (popmax 0.0132%, sas); Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu60Phe (c.178C>T)?

CDKN2A p.Leu60Phe (c.178C>T) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu60Phe (c.178C>T) in the general population?

CDKN2A p.Leu60Phe (c.178C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Leu60Phe

c.178C>T · rs769257927 · VCV532286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.114	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.66, phastCons 1
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,058 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000812% 13/1,601,950 alleles · ultra-rare exomes 13/1,449,642 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,588
Remaining individualsnot grpmax-eligible	0.0016%	62,324

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.Leu60Phe
Coding: c.178C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs769257927
Type: single nucleotide variant
Location: chr9:21994154 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 60: an α-helix; a UniProt-annotated variant site (in); a UniProt-annotated variant site (in melanoma; loss of cdk4 binding); the 'interaction with cdk5rap3 and mdm2' region; 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: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Ala60= Uncertain significance ★★ same residue
CDKN2A p.Ala60Thr Uncertain significance ★★ same residue
CDKN2A p.Ala60Val Uncertain significance ★★ same residue
CDKN2A p.Leu60Ile Uncertain significance ★★ same residue
CDKN2A p.Ala60Glu Likely pathogenic ★ same residue
CDKN2A p.Ala60Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala60Ser Uncertain significance ★ ⚠ same residue
CDKN2A p.Leu60Arg 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-leu60phe (accessed [today's date]).

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