Is CDKN2A p.His66Arg (c.197A>G) pathogenic?

CDKN2A p.His66Arg (c.197A>G) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1748); Rare (popmax 0.669%, eas); Associated with familial melanoma.

What condition is associated with CDKN2A p.His66Arg (c.197A>G)?

CDKN2A p.His66Arg (c.197A>G) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.His66Arg (c.197A>G) in the general population?

CDKN2A p.His66Arg (c.197A>G) is rare (popmax 0.669%, eas) (gnomAD).

How is Familial melanoma inherited?

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

What do computational predictors say about CDKN2A p.His66Arg (c.197A>G)?

AlphaMissense predicts likely benign (score 0.1748) — an in-silico prediction, not a clinical call.

CDKN2A p.His66Arg

c.197A>G · rs756750256 · VCV246117

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1748 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.1748	likely benign
REVEL	0.605	indeterminate
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	18.29	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.669% East Asian · 298/44,526 alleles

Filtering AF 0.607% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.582%

Overall 0.019% 303/1,594,708 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.669%	149
Remaining individualsnot grpmax-eligible	0.00807%	12,391

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.His66Arg
Coding: c.197A>G
MANE Select: NM_000077
dbSNP: rs756750256
Type: single nucleotide variant
Location: chr9:21971162 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 66: a UniProt-annotated variant site (in non-small cell lung carcinoma); the 'disordered' 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.His66Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.His66Pro Uncertain significance ★★ ⚠ same residue
CDKN2A p.His66= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.His66Asp Uncertain significance ★ ⚠ same residue
CDKN2A p.His66Tyr Uncertain significance ★ ⚠ same residue
CDKN2A p.His66fs Pathogenic ★ 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-his66arg (accessed [today's date]).

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