Is CDKN2A p.Ala134Pro (c.400G>C) pathogenic?

CDKN2A p.Ala134Pro (c.400G>C) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-07). AlphaMissense: likely benign (0.1837); Very rare (popmax 0.00667%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala134Pro (c.400G>C)?

CDKN2A p.Ala134Pro (c.400G>C) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Ala134Pro (c.400G>C) in the general population?

CDKN2A p.Ala134Pro (c.400G>C) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about CDKN2A p.Ala134Pro (c.400G>C)?

AlphaMissense predicts likely benign (score 0.1837) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala134Pro

c.400G>C · rs372599739 · VCV495536

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1837	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -4
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	0.961	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 0.00667% African / African-American · 5/74,936 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,611,668 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.Ala134Pro
Coding: c.400G>C
MANE Select: NM_000077
dbSNP: rs372599739
Type: single nucleotide variant
Location: chr9:21970959 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 134: a UniProt-annotated variant site (in non-small cell lung carcinoma)

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: familial melanoma

Similar variants

CDKN2A p.Ala134Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala134Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala134= Likely benign ★★ same residue
CDKN2A p.Ala134Gly Uncertain significance ★ ⚠ 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-ala134pro (accessed [today's date]).

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