Microcephaly, short stature, and impaired glucose metabolism 2

Summary

Microcephaly, short stature, and impaired glucose metabolism 2 (MONDO:0014785) is a disease caused by PPP1R15B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PPP1R15B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly, short stature, and impaired glucose metabolism 2
Mondo ID	MONDO:0014785
OMIM	616817
UMLS	C4225195
MedGen	906140
GARD	0018460
Is cancer (heuristic)	no

Also known as: microcephaly, short stature, and impaired glucose metabolism 2 · microcephaly, short stature, and impaired glucose metabolism 2; MSSGM2 · microcephaly, short stature, and impaired glucose metabolism caused by mutation in PPP1R15B · microcephaly, short stature, and impaired glucose metabolism type 2 · MSSGM2 · PPP1R15B microcephaly, short stature, and impaired glucose metabolism

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › microcephaly, short stature, and impaired glucose metabolism › microcephaly, short stature, and impaired glucose metabolism 2

Related subtypes (1): microcephaly, short stature, and impaired glucose metabolism 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
222030	NM_032833.5(PPP1R15B):c.1972C>T (p.Arg658Cys)	PPP1R15B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1975144	NM_032833.5(PPP1R15B):c.733A>G (p.Ser245Gly)	PPP1R15B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435223	NM_032833.5(PPP1R15B):c.1733C>G (p.Ser578Ter)	PPP1R15B	Uncertain significance	criteria provided, single submitter
2435224	NM_032833.5(PPP1R15B):c.644A>G (p.Asn215Ser)	PPP1R15B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376361	NM_032833.5(PPP1R15B):c.1378G>A (p.Asp460Asn)	PPP1R15B	Uncertain significance	criteria provided, single submitter
587627	NM_032833.5(PPP1R15B):c.25C>G (p.Arg9Gly)	PPP1R15B	Uncertain significance	criteria provided, multiple submitters, no conflicts
4820205	NM_032833.5(PPP1R15B):c.771C>T (p.Ser257=)	PPP1R15B	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PPP1R15B	Strong	Autosomal recessive	microcephaly, short stature, and impaired glucose metabolism 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPP1R15B	Orphanet:391408	Primary microcephaly-mild intellectual disability-young-onset diabetes syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PPP1R15B	HGNC:14951	ENSG00000158615	Q5SWA1	Protein phosphatase 1 regulatory subunit 15B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPP1R15B	Protein phosphatase 1 regulatory subunit 15B	Maintains low levels of EIF2S1 phosphorylation in unstressed cells by promoting its dephosphorylation by PP1.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPP1R15B	Other/Unknown	no		Prot_Pase1_reg-su15B_N, Prot_Pase1_reg-su15A/B_C, PPP1R15

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
ileal mucosa	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPP1R15B	255	ubiquitous	marker	ileal mucosa, kidney epithelium, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPP1R15B	960

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPP1R15B	Q5SWA1	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ER overload response	1	1532.0×	0.002	PPP1R15B
negative regulation of PERK-mediated unfolded protein response	1	1404.3×	0.002	PPP1R15B
negative regulation of protein phosphorylation	1	581.1×	0.003	PPP1R15B
response to hydrogen peroxide	1	468.1×	0.003	PPP1R15B
regulation of translation	1	218.9×	0.005	PPP1R15B
response to endoplasmic reticulum stress	1	166.8×	0.006	PPP1R15B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPP1R15B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PPP1R15B	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PPP1R15B

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PPP1R15B	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.