Is CDKN2A p.His26Arg (c.77A>G) pathogenic?

CDKN2A p.His26Arg (c.77A>G) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-09). Very rare (popmax 0.0099%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.His26Arg (c.77A>G)?

CDKN2A p.His26Arg (c.77A>G) is associated with hereditary neoplastic syndrome, melanoma and neural system tumor syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.His26Arg (c.77A>G) in the general population?

CDKN2A p.His26Arg (c.77A>G) is very rare (popmax 0.0099%, sas) (gnomAD).

CDKN2A p.His26Arg

c.77A>G · rs780803896 · VCV1362912

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0099%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.086	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.087	GERP -0.84, phastCons 0.015
Overall
CADD	15.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0099% South Asian · 9/90,928 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.000756% 11/1,454,514 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0099%	10,103
Remaining individualsnot grpmax-eligible	0.00161%	62,266
European (non-Finnish)	8.48e-05%	1,178,607

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.His26Arg
Coding: c.77A>G
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs780803896
Type: single nucleotide variant
Location: chr9:21994255 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma and neural system tumor syndrome familial melanoma

Similar variants

CDKN2A p.Glu26Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Glu26= Benign/Likely benign ★★ same residue
CDKN2A p.His26= 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-his26arg (accessed [today's date]).

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