Is CDKN2A p.Asp74Ala (c.221A>C) pathogenic?

CDKN2A p.Asp74Ala (c.221A>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). AlphaMissense: likely pathogenic (0.8943); Low-frequency (popmax 2.43%, mid); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Asp74Ala (c.221A>C)?

CDKN2A p.Asp74Ala (c.221A>C) is associated with melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Asp74Ala (c.221A>C) in the general population?

CDKN2A p.Asp74Ala (c.221A>C) is low-frequency (popmax 2.43%, mid) (gnomAD).

What do computational predictors say about CDKN2A p.Asp74Ala (c.221A>C)?

AlphaMissense predicts likely pathogenic (score 0.8943) — an in-silico prediction, not a clinical call.

CDKN2A p.Asp74Ala

Q: How is Familial atypical multiple mole melanoma syndrome inherited?

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

c.221A>C · rs200429615 · VCV802463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8943 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.43%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.8943	likely pathogenic
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	26.1	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 2.43% Middle Eastern · 112/4,602 alleles

Filtering AF 2.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.93%

Overall 0.0169% 265/1,565,272 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.43%	41
Ashkenazi Jewishnot grpmax-eligible	0.0459%	2,180
Admixed American	0.0385%	2,595
South Asian	0.0244%	4,094
Remaining individualsnot grpmax-eligible	0.023%	4,356
African / African-American	0.00951%	10,519
East Asian	0.00702%	14,247
European (non-Finnish)	0.0061%	16,400
Finnishnot grpmax-eligible	0.00609%	16,408

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.Asp74Ala
Coding: c.221A>C
MANE Select: NM_000077
dbSNP: rs200429615
Type: single nucleotide variant
Location: chr9:21971138 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 74: a UniProt-annotated variant site (in a bladder tumor); a UniProt-annotated variant site (in a biliary tract tumor); a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); the 'disordered' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

melanoma-pancreatic cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Asp74His Uncertain significance ★ ⚠ same residue
CDKN2A p.Asp74fs Likely pathogenic ★ same residue
CDKN2A p.Asp74Asn Uncertain significance ★★ ⚠ same residue
CDKN2A p.Asp74Glu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Asp74= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Asp74Val Conflicting classifications of pathogenicity ★ ⚠ 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-asp74ala (accessed [today's date]).

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