Is CDKN2A p.Phe23= (c.69C>T) pathogenic?

CDKN2A p.Phe23= (c.69C>T) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.0254%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Phe23= (c.69C>T)?

CDKN2A p.Phe23= (c.69C>T) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Phe23= (c.69C>T) in the general population?

CDKN2A p.Phe23= (c.69C>T) is ultra-rare (popmax 0.0254%, nfe) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Phe23=

c.69C>T · rs374360796 · VCV136717

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, nfe)

Conditions

familial melanoma

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 3.5	GERP -0.3, phastCons 1
Overall
CADD	13.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% European (non-Finnish) · 299/1,177,660 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.022%

Overall 0.0203% 326/1,605,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0254%	3,939
Remaining individualsnot grpmax-eligible	0.0241%	4,146
Middle Eastern	0.0165%	6,072
Admixed American	0.00837%	11,951
Finnishnot grpmax-eligible	0.00507%	19,712
African / African-American	0.00401%	24,936

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.Phe23=
Coding: c.69C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs374360796
Type: single nucleotide variant
Location: chr9:21994263 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 23: a UniProt-annotated variant site (in a pancreas tumor and a melanoma; loss of cdk4 binding); 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

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.Gly23Arg Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly23Asp Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly23Cys Likely pathogenic ★★ same residue
CDKN2A p.Gly23Ser Likely pathogenic ★★ same residue
CDKN2A p.Phe23Leu Uncertain significance ★★ same residue
CDKN2A p.Gly23= Likely benign ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G 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-phe23 (accessed [today's date]).

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