Is CDKN2A p.Gly67Arg (c.199G>C) pathogenic?

CDKN2A p.Gly67Arg (c.199G>C) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.5034); Very rare (popmax 0.00168%, amr); Associated with familial melanoma.

What condition is associated with CDKN2A p.Gly67Arg (c.199G>C)?

CDKN2A p.Gly67Arg (c.199G>C) is associated with familial melanoma, melanoma and neural system tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Gly67Arg (c.199G>C) in the general population?

CDKN2A p.Gly67Arg (c.199G>C) is very rare (popmax 0.00168%, amr) (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.Gly67Arg (c.199G>C)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

CDKN2A p.Gly67Arg

c.199G>C · rs758389471 · VCV216272

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -11.74	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.4	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 0.00168% Admixed American · 1/59,408 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000277% 4/1,442,608 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,408
European (non-Finnish)	0.000255%	392,445

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.Gly67Arg
Coding: c.199G>C
MANE Select: NM_000077
dbSNP: rs758389471
Type: single nucleotide variant
Location: chr9:21971160 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 67: a UniProt-annotated variant site (in melanoma; loss of cdk4 binding); a UniProt-annotated variant site (in cmm2; partial loss of cdk4 binding); 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 and neural system tumor 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.Gly67= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Gly67Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Gly67Cys Uncertain significance ★ ⚠ same residue
CDKN2A p.Gly67Ser Conflicting classifications of pathogenicity ★ ⚠ 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-gly67arg (accessed [today's date]).

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