Is CDKN1B p.Pro69Ser (c.205C>T) pathogenic?

CDKN1B p.Pro69Ser (c.205C>T) is classified Uncertain significance in CDKN1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.9931); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN1B p.Pro69Ser (c.205C>T)?

CDKN1B p.Pro69Ser (c.205C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 4 (ClinVar).

How common is CDKN1B p.Pro69Ser (c.205C>T) in the general population?

CDKN1B p.Pro69Ser (c.205C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CDKN1B p.Pro69Ser (c.205C>T)?

AlphaMissense predicts likely pathogenic (score 0.9931) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro69Ser

c.205C>T · rs1388968180 · VCV864336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9931	likely pathogenic · top 3% in CDKN1B
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -12.08	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	26.1	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 0.0011% South Asian · 1/91,088 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000619% 10/1,614,258 alleles · very rare exomes 10/1,461,890 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,508
Finnishnot grpmax-eligible	0.00156%	64,044
South Asiangrpmax	0.0011%	91,088
European (non-Finnish)	0.000508%	196,674

Ashkenazi Jewish 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: CDKN1B
Protein: p.Pro69Ser
Coding: c.205C>T
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 4

Similar variants

CDKN1B p.Pro69Ala Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro69His Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro69Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN1B p.Pro69= Likely benign ★ same residue
CDKN1B p.Pro69_Leu70insTer Pathogenic ★ same residue
CDKN1B p.Pro69_Leu70insPro Uncertain significance ★ same residue
CDKN1B p.Arg154Ter Pathogenic ★★ same condition
CDKN1B p.Arg5Ter Pathogenic/Likely 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-pro69ser (accessed [today's date]).

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