Is CDKN1B p.Pro91Ser (c.271C>T) pathogenic?

CDKN1B p.Pro91Ser (c.271C>T) is classified Conflicting classifications of pathogenicity in CDKN1B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.1221); Very rare (popmax 0.00878%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN1B p.Pro91Ser (c.271C>T)?

CDKN1B p.Pro91Ser (c.271C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 4 (ClinVar).

How common is CDKN1B p.Pro91Ser (c.271C>T) in the general population?

CDKN1B p.Pro91Ser (c.271C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about CDKN1B p.Pro91Ser (c.271C>T)?

AlphaMissense predicts likely benign (score 0.1221) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro91Ser

c.271C>T · rs769828807 · VCV821710

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1221	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 0.61, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 1,103 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	21.0	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 0.00878% South Asian · 8/91,090 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000805% 13/1,614,220 alleles · very rare exomes 13/1,461,852 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.000339%	295,013

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.Pro91Ser
Coding: c.271C>T
MANE Select: NM_004064
dbSNP: rs769828807
Type: single nucleotide variant
Location: chr12:12718110 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI 0.24 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.08 · 19 PDB
Residue 91: the 'interaction with cdk2' region; the 'disordered' region; an α-helix

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.Pro91Ala Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro91His Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro91Leu Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro91= Likely benign ★★ same residue
CDKN1B p.Pro91Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN1B p.Pro91Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN1B p.Pro91fs Pathogenic ★ same residue
CDKN1B p.Arg154Ter 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-pro91ser (accessed [today's date]).

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