Is CDKN2A p.Pro48Thr (c.142C>A) pathogenic?

CDKN2A p.Pro48Thr (c.142C>A) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.8084); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro48Thr (c.142C>A)?

CDKN2A p.Pro48Thr (c.142C>A) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro48Thr (c.142C>A) in the general population?

CDKN2A p.Pro48Thr (c.142C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Pro48Thr (c.142C>A)?

AlphaMissense predicts likely pathogenic (score 0.8084) — an in-silico prediction, not a clinical call.

CDKN2A p.Pro48Thr

c.142C>A · rs786204195 · VCV188286

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8084	likely pathogenic ✓ concordant with ClinVar
REVEL	0.685	pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.017, phastCons 0.94
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	20.7	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,714 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.Pro48Thr
Coding: c.142C>A
MANE Select: NM_000077
dbSNP: rs786204195
Type: single nucleotide variant
Location: chr9:21974686 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 48: an α-helix; a UniProt-annotated variant site (in cmm2; also found in head and neck tumor; somatic mutation); the 'interaction with cdk5rap3 and mdm2' 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: familial melanoma

Similar variants

CDKN2A p.Pro48Leu Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Pro48Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Met48Leu Uncertain significance ★ same residue
CDKN2A p.Pro48Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro48= Likely benign ★ 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

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-pro48thr (accessed [today's date]).

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