Is CDKN1B p.Pro91Arg (c.272C>G) pathogenic?

CDKN1B p.Pro91Arg (c.272C>G) is classified Conflicting classifications of pathogenicity in CDKN1B (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-03). AlphaMissense: likely benign (0.1587); Very rare (popmax 0.000593%, nfe); Associated with multiple endocrine neoplasia type 4.

What condition is associated with CDKN1B p.Pro91Arg (c.272C>G)?

CDKN1B p.Pro91Arg (c.272C>G) is associated with multiple endocrine neoplasia type 4, hereditary neoplastic syndrome (ClinVar).

How common is CDKN1B p.Pro91Arg (c.272C>G) in the general population?

CDKN1B p.Pro91Arg (c.272C>G) is very rare (popmax 0.000593%, 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.Pro91Arg (c.272C>G)?

AlphaMissense predicts likely benign (score 0.1587) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro91Arg

c.272C>G · rs768793049 · VCV469012

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple endocrine neoplasia type 4

Computational evidence

Protein change
AlphaMissense	0.1587	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -8.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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	24.4	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 0.000593% European (non-Finnish) · 7/1,180,046 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,200 alleles · very rare exomes 8/1,461,852 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000593%	168,578

Remaining individuals 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.Pro91Arg
Coding: c.272C>G
MANE Select: NM_004064
dbSNP: rs768793049
Type: single nucleotide variant
Location: chr12:12718111 (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

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

Also linked: hereditary neoplastic syndrome

For Multiple endocrine neoplasia type 4 (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

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.Pro91Ser 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-pro91arg (accessed [today's date]).

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