Is CDKN1B p.Pro95Ser (c.283C>T) pathogenic?

CDKN1B p.Pro95Ser (c.283C>T) is classified Uncertain significance in CDKN1B (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.0928); Ultra-rare (popmax 0.0267%, eas); Associated with Familial hyperparathyroidism or Hypocalciuric hypercalcaemia.

What condition is associated with CDKN1B p.Pro95Ser (c.283C>T)?

CDKN1B p.Pro95Ser (c.283C>T) is associated with Familial hyperparathyroidism or Hypocalciuric hypercalcaemia, multiple endocrine neoplasia type 4, hereditary neoplastic syndrome (ClinVar).

How common is CDKN1B p.Pro95Ser (c.283C>T) in the general population?

CDKN1B p.Pro95Ser (c.283C>T) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about CDKN1B p.Pro95Ser (c.283C>T)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro95Ser

c.283C>T · rs188579132 · VCV404265

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Familial hyperparathyroidism or Hypocalciuric hypercalcaemia

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -7.52	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 7.5	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	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0267% East Asian · 12/44,882 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0145%

Overall 0.0145% 234/1,614,186 alleles · ultra-rare exomes 221/1,461,804 · genomes 13/152,382 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
European (non-Finnish)	0.0172%	5,813
Admixed American	0.0117%	8,577
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.00549%	18,218
African / African-American	0.00266%	37,538

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.Pro95Ser
Coding: c.283C>T
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

Familial hyperparathyroidism or Hypocalciuric hypercalcaemia

Also linked: multiple endocrine neoplasia type 4 hereditary neoplastic syndrome

Similar variants

CDKN1B p.Pro95Arg Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro95His Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro95= Likely benign ★★ same residue
CDKN1B p.Pro95Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro95ser (accessed [today's date]).

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