Is CDKN1B p.Ser56Arg (c.168C>G) pathogenic?

CDKN1B p.Ser56Arg (c.168C>G) is classified Uncertain significance in CDKN1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-31). AlphaMissense: likely pathogenic (0.8728); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN1B p.Ser56Arg (c.168C>G)?

CDKN1B p.Ser56Arg (c.168C>G) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 4 (ClinVar).

How common is CDKN1B p.Ser56Arg (c.168C>G) in the general population?

CDKN1B p.Ser56Arg (c.168C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN1B p.Ser56Arg (c.168C>G)?

AlphaMissense predicts likely pathogenic (score 0.8728) — an in-silico prediction, not a clinical call.

CDKN1B p.Ser56Arg

c.168C>G · rs35456792 · VCV2562089

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8728 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8728	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.62, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 1,103 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	22.0	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

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.Ser56Arg
Coding: c.168C>G
MANE Select: NM_004064
dbSNP: rs35456792
Type: single nucleotide variant
Location: chr12:12718007 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI 0.24 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.08 · 19 PDB
Residue 56: the 'interaction with cdk2' 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.Ser56Thr Uncertain significance ★★ ⚠ same residue
CDKN1B p.Ser56= Benign/Likely benign ★★ same residue
CDKN1B p.Ser56Cys Uncertain significance ★ ⚠ same residue
CDKN1B p.Ser56fs Pathogenic ★ 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

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-ser56arg (accessed [today's date]).

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