Is CDKN2A p.Ala57Val (c.170C>T) pathogenic?

CDKN2A p.Ala57Val (c.170C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1532); Ultra-rare (popmax 0.0115%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala57Val (c.170C>T)?

CDKN2A p.Ala57Val (c.170C>T) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, Li-Fraumeni syndrome (ClinVar).

How common is CDKN2A p.Ala57Val (c.170C>T) in the general population?

CDKN2A p.Ala57Val (c.170C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Ala57Val (c.170C>T)?

AlphaMissense predicts likely benign (score 0.1532) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala57Val

c.170C>T · rs372266620 · VCV220562

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1532 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1532	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -8.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	12.35	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 0.0115% European (non-Finnish) · 136/1,178,892 alleles

Filtering AF 0.00995% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.0102% 163/1,597,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0201%	4,978
Remaining individualsnot grpmax-eligible	0.0193%	5,187
European (non-Finnish)grpmax	0.0115%	8,668
Admixed American	0.00669%	14,956
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,552

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala57Val
Coding: c.170C>T
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-pancreatic cancer syndrome Li-Fraumeni syndrome familial melanoma

Similar variants

CDKN2A p.Ala57Asp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala57Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gln57Arg Uncertain significance ★★ same residue
CDKN2A p.Gln57Ter Pathogenic ★ 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

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-ala57val (accessed [today's date]).

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