Is CDKN2A p.His26= (c.78C>T) pathogenic?

CDKN2A p.His26= (c.78C>T) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-12). Ultra-rare (popmax 0.0156%, eas); Associated with familial melanoma.

What condition is associated with CDKN2A p.His26= (c.78C>T)?

CDKN2A p.His26= (c.78C>T) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.His26= (c.78C>T) in the general population?

CDKN2A p.His26= (c.78C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.His26=

c.78C>T · rs756946306 · VCV1140549

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

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 -0.81	GERP -3.1
Overall
CADD	7.339	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,786 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000825% 12/1,454,518 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,398
Remaining individualsnot grpmax-eligible	0.00161%	62,272
European (non-Finnish)	0.000339%	294,689

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.His26=
Coding: c.78C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs756946306
Type: single nucleotide variant
Location: chr9:21994254 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 26: an α-helix; a UniProt-annotated variant site (in a biliary tract tumor); 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.Glu26Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.His26Arg Uncertain significance ★★ same residue
CDKN2A p.Glu26= Benign/Likely benign ★★ same residue
CDKN2A p.Glu26Ter Pathogenic ★ same residue
CDKN2A p.Glu26Ala Uncertain significance ★ ⚠ same residue
CDKN2A p.His26Tyr Uncertain significance ★ 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-his26 (accessed [today's date]).

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