Is CDKN2A p.Pro38Ser (c.112C>T) pathogenic?

CDKN2A p.Pro38Ser (c.112C>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.7699); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro38Ser (c.112C>T)?

CDKN2A p.Pro38Ser (c.112C>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro38Ser (c.112C>T) in the general population?

CDKN2A p.Pro38Ser (c.112C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Pro38Ser (c.112C>T)?

AlphaMissense predicts likely pathogenic (score 0.7699) — an in-silico prediction, not a clinical call.

CDKN2A p.Pro38Ser

c.112C>T · rs1587339752 · VCV822217

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7699	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -12.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,804 alleles

Overall 6.2e-05% 1/1,611,850 alleles · very rare exomes 1/1,459,646 · genomes 0/152,204 · joint denominator

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.Pro38Ser
Coding: c.112C>T
MANE Select: NM_000077
dbSNP: rs1587339752
Type: single nucleotide variant
Location: chr9:21974716 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 38: 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.Gly38Glu Uncertain significance ★★ same residue
CDKN2A p.Pro38Ala Uncertain significance ★★ ⚠ same residue
CDKN2A p.Pro38= Benign/Likely benign ★★ same residue
CDKN2A p.Gly38Ala Uncertain significance ★ same residue
CDKN2A p.Gly38Arg Uncertain significance ★ same residue
CDKN2A p.Gly38Val Uncertain significance ★ same residue
CDKN2A p.Pro38Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Gly38= 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-pro38ser (accessed [today's date]).

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