Is CDKN2A p.Gly67Asp (c.200G>A) pathogenic?

CDKN2A p.Gly67Asp (c.200G>A) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-10-30). AlphaMissense: ambiguous (0.4936); Very rare (popmax 0.000255%, nfe); Associated with CDKN2A-related disorder.

What condition is associated with CDKN2A p.Gly67Asp (c.200G>A)?

CDKN2A p.Gly67Asp (c.200G>A) is associated with CDKN2A-related disorder, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Gly67Asp (c.200G>A) in the general population?

CDKN2A p.Gly67Asp (c.200G>A) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Gly67Asp (c.200G>A)?

AlphaMissense predicts ambiguous (score 0.4936) — an in-silico prediction, not a clinical call.

CDKN2A p.Gly67Asp

c.200G>A · rs863224605 · VCV216273

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CDKN2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.4936	ambiguous
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -13.02	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 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.1	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 0.000255% European (non-Finnish) · 3/1,177,374 alleles

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

Overall 0.000188% 3/1,594,848 alleles · very rare

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.Gly67Asp
Coding: c.200G>A
MANE Select: NM_000077
dbSNP: rs863224605
Type: single nucleotide variant
Location: chr9:21971159 (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

CDKN2A-related disorder

Also linked: hereditary neoplastic syndrome familial melanoma

Similar variants

CDKN2A p.Gly67= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Gly67Arg 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-gly67asp (accessed [today's date]).

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