Is CDKN2A p.His123= (c.369T>C) pathogenic?

CDKN2A p.His123= (c.369T>C) is classified Likely benign in CDKN2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-04-09). Ultra-rare (popmax 0.0133%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.His123= (c.369T>C)?

CDKN2A p.His123= (c.369T>C) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.His123= (c.369T>C) in the general population?

CDKN2A p.His123= (c.369T>C) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

CDKN2A p.His123=

c.369T>C · rs6413463 · VCV220829

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

hereditary neoplastic syndrome

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 2.7	GERP 0.18, phastCons 1
Overall
CADD	4.752	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,986 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000932% 15/1,610,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,498
South Asian	0.0022%	45,516
Remaining individualsnot grpmax-eligible	0.0016%	62,382
European (non-Finnish)	0.000339%	294,997

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.His123=
Coding: c.369T>C
MANE Select: NM_000077
dbSNP: rs6413463
Type: single nucleotide variant
Location: chr9:21970990 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 123: a UniProt-annotated variant site (in leukemia); the 'disordered' 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-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.His123Arg Uncertain significance ★ ⚠ same residue
CDKN2A p.His123Gln Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.His123Tyr Uncertain significance ★ ⚠ same residue
CDKN2A p.His123fs Pathogenic ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A Pathogenic ★★ same condition
CDKN2A c.151-1G>C 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-his123 (accessed [today's date]).

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