Is CDKN2A p.Phe5Ile (c.13T>A) pathogenic?

CDKN2A p.Phe5Ile (c.13T>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-14). Very rare (popmax 0.00336%, amr); Associated with familial melanoma.

What condition is associated with CDKN2A p.Phe5Ile (c.13T>A)?

CDKN2A p.Phe5Ile (c.13T>A) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Phe5Ile (c.13T>A) in the general population?

CDKN2A p.Phe5Ile (c.13T>A) is very rare (popmax 0.00336%, amr) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Phe5Ile

c.13T>A · rs776987532 · VCV245816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.43	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.5, phastCons 1
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% Admixed American · 2/59,474 alleles

Filtering AF 0.000558% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000498% 8/1,605,614 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,737
East Asian	0.00224%	44,726
Remaining individualsnot grpmax-eligible	0.00161%	62,070
European (non-Finnish)	0.00034%	294,333

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.Phe5Ile
Coding: c.13T>A
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs776987532
Type: single nucleotide variant
Location: chr9:21994319 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 5: 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

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.Ala5Glu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala5Thr Uncertain significance ★★ same residue
CDKN2A p.Ala5Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Phe5Leu Uncertain significance ★★ same residue
CDKN2A p.Phe5Tyr Uncertain significance ★★ same residue
CDKN2A p.Ala5= Benign/Likely benign ★★ same residue
CDKN2A p.Phe5= Benign/Likely benign ★★ same residue
CDKN2A p.Phe5Ser 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-phe5ile (accessed [today's date]).

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