Is CDKN1B p.Pro69Ala (c.205C>G) pathogenic?

CDKN1B p.Pro69Ala (c.205C>G) is classified Uncertain significance in CDKN1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-13). AlphaMissense: likely pathogenic (0.8896); Very rare (popmax 8.47e-05%, nfe); Associated with multiple endocrine neoplasia type 4.

What condition is associated with CDKN1B p.Pro69Ala (c.205C>G)?

CDKN1B p.Pro69Ala (c.205C>G) is associated with multiple endocrine neoplasia type 4 (ClinVar).

How common is CDKN1B p.Pro69Ala (c.205C>G) in the general population?

CDKN1B p.Pro69Ala (c.205C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Multiple endocrine neoplasia type 4 inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN1B p.Pro69Ala (c.205C>G)?

AlphaMissense predicts likely pathogenic (score 0.8896) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro69Ala

c.205C>G · rs1388968180 · VCV858127

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8896 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 4

Computational evidence

Protein change
AlphaMissense	0.8896	likely pathogenic
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -10.97	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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 1,103 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	25.2	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 8.47e-05% European (non-Finnish) · 1/1,180,046 alleles

Overall 6.19e-05% 1/1,614,258 alleles · very rare exomes 1/1,461,890 · genomes 0/152,368 · 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: CDKN1B
Protein: p.Pro69Ala
Coding: c.205C>G
MANE Select: NM_004064
dbSNP: rs1388968180
Type: single nucleotide variant
Location: chr12:12718044 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI 0.24 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.08 · 19 PDB
Residue 69: a UniProt-annotated variant site (found in a patient with multiple endocrine tumors; germline mutation; reduced expression levels; shows impaired binding to cdk2); the 'interaction with cdk2' region

Full CDKN1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple endocrine neoplasia type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 4 (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

Similar variants

CDKN1B p.Pro69His Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro69Ser Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro69Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN1B p.Pro69= Likely benign ★ same residue
CDKN1B p.Arg154Ter Pathogenic ★★ same condition
CDKN1B p.Arg5Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1B p.Gln104Ter Pathogenic ★★ same condition
CDKN1B p.Gln107Ter 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/cdkn1b-p-pro69ala (accessed [today's date]).

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