Is CDKN2A p.Ala57Asp (c.170C>A) pathogenic?

CDKN2A p.Ala57Asp (c.170C>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-31). AlphaMissense: ambiguous (0.4412); Ultra-rare (popmax 0.0662%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala57Asp (c.170C>A)?

CDKN2A p.Ala57Asp (c.170C>A) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Ala57Asp (c.170C>A) in the general population?

CDKN2A p.Ala57Asp (c.170C>A) is ultra-rare (popmax 0.0662%, mid) (gnomAD).

What do computational predictors say about CDKN2A p.Ala57Asp (c.170C>A)?

AlphaMissense predicts ambiguous (score 0.4412) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala57Asp

c.170C>A · rs372266620 · VCV483325

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0662%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4412	ambiguous
REVEL	0.442	indeterminate
SaProt	LLR -8.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP 0.24
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	17.4	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 0.0662% Middle Eastern · 4/6,044 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000689% 11/1,597,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0662%	1,511
Admixed American	0.00334%	29,913
Remaining individualsnot grpmax-eligible	0.00321%	31,119
African / African-American	0.00134%	74,860
European (non-Finnish)	0.00017%	589,445

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.Ala57Asp
Coding: c.170C>A
MANE Select: NM_000077
dbSNP: rs372266620
Type: single nucleotide variant
Location: chr9:21971189 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 57: an α-helix; a UniProt-annotated variant site (in pancreas carcinoma; somatic mutation; partial loss of cdk4 binding); the 'interaction with cdk5rap3 and mdm2' region; the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome familial melanoma

Similar variants

CDKN2A p.Ala57Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gln57Arg Uncertain significance ★★ same residue
CDKN2A p.Ala57Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Gln57His Uncertain significance ★ same residue
CDKN2A p.Ala57= Likely benign ★ same residue
CDKN2A p.Ala57Thr Likely benign ★ same residue
CDKN2A p.Gln57= Likely benign ★ same residue
CDKN2A p.Gln57Ter Pathogenic ★ same residue

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-ala57asp (accessed [today's date]).

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