Is CDKN2A p.Asp74His (c.220G>C) pathogenic?

CDKN2A p.Asp74His (c.220G>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). AlphaMissense: likely pathogenic (0.8861); Very rare (popmax 0.00514%, amr); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Asp74His (c.220G>C)?

CDKN2A p.Asp74His (c.220G>C) is associated with melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Asp74His (c.220G>C) in the general population?

CDKN2A p.Asp74His (c.220G>C) is very rare (popmax 0.00514%, amr) (gnomAD).

What do computational predictors say about CDKN2A p.Asp74His (c.220G>C)?

AlphaMissense predicts likely pathogenic (score 0.8861) — an in-silico prediction, not a clinical call.

CDKN2A p.Asp74His

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.220G>C · rs760640852 · VCV802464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00514%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.8861	likely pathogenic
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -9.65	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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	26.4	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 0.00514% Admixed American · 3/58,382 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000678%

Overall 0.000278% 4/1,438,540 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00514%	19,461
European (non-Finnish)	8.51e-05%	1,175,299

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.Asp74His
Coding: c.220G>C
MANE Select: NM_000077
dbSNP: rs760640852
Type: single nucleotide variant
Location: chr9:21971139 (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.Asp74Ala 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-asp74his (accessed [today's date]).

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