Is CDKN1B p.Pro85His (c.254C>A) pathogenic?

CDKN1B p.Pro85His (c.254C>A) is classified Uncertain significance in CDKN1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: likely pathogenic (0.9688); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN1B p.Pro85His (c.254C>A)?

CDKN1B p.Pro85His (c.254C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN1B p.Pro85His (c.254C>A) in the general population?

CDKN1B p.Pro85His (c.254C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN1B p.Pro85His (c.254C>A)?

AlphaMissense predicts likely pathogenic (score 0.9688) — an in-silico prediction, not a clinical call.

CDKN1B p.Pro85His

c.254C>A · VCV3489621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9688 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9688	likely pathogenic · top 6% in CDKN1B
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -11.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	27.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN1B
Protein: p.Pro85His
Coding: c.254C>A
MANE Select: NM_004064
Type: single nucleotide variant
Location: chr12:12718093 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI 0.24 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.08 · 19 PDB
Residue 85: the 'interaction with cdk2' region; the 'disordered' 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

Similar variants

CDKN1B p.Pro85Leu Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro85Ser Uncertain significance ★★ ⚠ same residue
CDKN1B p.Pro85= Likely benign ★★ same residue
CDKN1B p.Arg154Ter Pathogenic ★★ same condition
CDKN1B p.Arg5Ter Pathogenic/Likely pathogenic ★★ same condition
CDKN1B p.Gln104Ter Pathogenic ★★ same condition
CDKN1B p.Gln107Ter Pathogenic ★★ same condition
CDKN1B p.Gln141Ter 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-pro85his (accessed [today's date]).

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