Is CDKN1B p.Pro95Ala (c.283C>G) pathogenic?

CDKN1B p.Pro95Ala (c.283C>G) is classified Conflicting classifications of pathogenicity in CDKN1B (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0446%, eas); Associated with multiple endocrine neoplasia type 4.

What condition is associated with CDKN1B p.Pro95Ala (c.283C>G)?

CDKN1B p.Pro95Ala (c.283C>G) is associated with multiple endocrine neoplasia type 4, hereditary neoplastic syndrome (ClinVar).

How common is CDKN1B p.Pro95Ala (c.283C>G) in the general population?

CDKN1B p.Pro95Ala (c.283C>G) is ultra-rare (popmax 0.0446%, eas) (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.Pro95Ala (c.283C>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro95Ala

c.283C>G · rs188579132 · VCV705103

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 4

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	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	20.2	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 0.0446% East Asian · 20/44,882 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00142% 23/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	8.47e-05%	1,180,045

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.Pro95Ala
Coding: c.283C>G
MANE Select: NM_004064
dbSNP: rs188579132
Type: single nucleotide variant
Location: chr12:12718122 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI 0.24 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.08 · 19 PDB
Residue 95: the 'disordered' 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

Also linked: hereditary neoplastic syndrome

For Multiple endocrine neoplasia type 4 (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

Similar variants

CDKN1B p.Pro95Arg Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro95His Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro95Ser Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro95= Likely benign ★★ same residue
CDKN1B p.Pro95Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN1B p.Arg154Ter Pathogenic ★★ same condition
CDKN1B p.Arg5Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1B p.Gln104Ter 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-pro95ala (accessed [today's date]).

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