Holoprosencephaly 12 with or without pancreatic agenesis

Summary

Holoprosencephaly 12 with or without pancreatic agenesis (MONDO:0032787) is a disease caused by CNOT1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CNOT1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 12 with or without pancreatic agenesis
Mondo ID	MONDO:0032787
OMIM	618500
DOID	DOID:0081398
UMLS	C5193131
MedGen	1684550
GARD	0025743
Is cancer (heuristic)	no

Also known as: holoprosencephaly 12, with or without pancreatic agenesis · HPE12

Data availability: 28 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 12 with or without pancreatic agenesis

Related subtypes (16): holoprosencephaly 3, holoprosencephaly 4, holoprosencephaly 2, holoprosencephaly 1, holoprosencephaly 6, holoprosencephaly 8, holoprosencephaly 7, chromosome 1q41-q42 deletion syndrome, holoprosencephaly 11, microform holoprosencephaly, lobar holoprosencephaly, alobar holoprosencephaly, holoprosencephaly 13, X-linked, holoprosencephaly 14, semilobar holoprosencephaly, holoprosencephaly 10

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

28 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 7 benign, 3 likely pathogenic, 3 pathogenic, 2 conflicting classifications of pathogenicity, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3382694	NM_016284.5(CNOT1):c.371_372dup (p.Gln125fs)	CNOT1	Pathogenic	criteria provided, single submitter
3767105	NM_016284.5(CNOT1):c.304C>T (p.Gln102Ter)	CNOT1	Pathogenic	criteria provided, single submitter
619606	NM_016284.5(CNOT1):c.1603C>T (p.Arg535Cys)	CNOT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3061856	NM_016284.5(CNOT1):c.3754_3756dup (p.Phe1252_Arg1253insPhe)	CNOT1	Likely pathogenic	criteria provided, single submitter
3256763	NM_016284.5(CNOT1):c.3634C>G (p.His1212Asp)	CNOT1	Likely pathogenic	no assertion criteria provided
3767970	NM_016284.5(CNOT1):c.3202-2dup	CNOT1	Likely pathogenic	criteria provided, single submitter
2200469	NM_016284.5(CNOT1):c.1328G>A (p.Arg443Gln)	CNOT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2646576	NM_016284.5(CNOT1):c.4434+194_4434+195del	CNOT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027850	NM_016284.5(CNOT1):c.5342A>G (p.Glu1781Gly)	CNOT1	Uncertain significance	criteria provided, single submitter
1319907	NM_016284.5(CNOT1):c.3509A>G (p.Tyr1170Cys)	CNOT1	Uncertain significance	no assertion criteria provided
1696441	NM_016284.5(CNOT1):c.-175+5G>A	CNOT1	Uncertain significance	criteria provided, single submitter
2431525	NM_016284.5(CNOT1):c.4255A>T (p.Thr1419Ser)	CNOT1	Uncertain significance	criteria provided, single submitter
2431824	NM_016284.5(CNOT1):c.4396T>G (p.Ser1466Ala)	CNOT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3370400	NM_016284.5(CNOT1):c.4205dup (p.Glu1403fs)	CNOT1	Uncertain significance	criteria provided, single submitter
3581126	NM_016284.5(CNOT1):c.3618A>C (p.Lys1206Asn)	CNOT1	Uncertain significance	criteria provided, single submitter
3581127	NM_016284.5(CNOT1):c.581G>T (p.Gly194Val)	CNOT1	Uncertain significance	criteria provided, single submitter
3671161	NM_016284.5(CNOT1):c.532A>G (p.Ile178Val)	CNOT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779106	NM_016284.5(CNOT1):c.4104G>A (p.Ala1368=)	CNOT1	Uncertain significance	criteria provided, single submitter
977381	NM_016284.5(CNOT1):c.1240A>G (p.Ile414Val)	CNOT1	Uncertain significance	criteria provided, single submitter
1217372	NM_016284.5(CNOT1):c.5896-5C>T	CNOT1	Benign	criteria provided, multiple submitters, no conflicts
1217373	NM_016284.5(CNOT1):c.4716C>T (p.Tyr1572=)	CNOT1	Benign	criteria provided, multiple submitters, no conflicts
1217374	NM_016284.5(CNOT1):c.4524G>A (p.Gln1508=)	CNOT1	Benign	criteria provided, single submitter
1217375	NM_016284.5(CNOT1):c.4128G>A (p.Leu1376=)	CNOT1	Benign	criteria provided, multiple submitters, no conflicts
1217376	NM_016284.5(CNOT1):c.4006+12A>G	CNOT1	Benign	criteria provided, multiple submitters, no conflicts
1217378	NM_016284.5(CNOT1):c.2919G>A (p.Gln973=)	CNOT1	Benign	criteria provided, multiple submitters, no conflicts
1217379	NM_016284.5(CNOT1):c.909A>G (p.Gly303=)	CNOT1	Benign	criteria provided, multiple submitters, no conflicts
4685523	NM_016284.5(CNOT1):c.3958A>G (p.Lys1320Glu)	CNOT1	Likely benign	criteria provided, single submitter
4819935	NM_016284.5(CNOT1):c.2333-1G>A	CNOT1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
CNOT1	Strong	Autosomal dominant	holoprosencephaly 12 with or without pancreatic agenesis	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNOT1	Orphanet:528084	Non-specific syndromic intellectual disability
CNOT1	Orphanet:556955	Pancreatic agenesis-holoprosencephaly 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
CNOT1	HGNC:7877	ENSG00000125107	A5YKK6	CCR4-NOT transcription complex subunit 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNOT1	CCR4-NOT transcription complex subunit 1	Scaffolding component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during tran…

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)
CNOT1	Other/Unknown	no		CCR4-Not_Not1_C, CNOT1_dom_4, CNOT1_CAF1_bind

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
left testis	1
primordial germ cell in gonad	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNOT1	295	ubiquitous	marker	primordial germ cell in gonad, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CNOT1	3,760

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNOT1	A5YKK6	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	519.1×	0.003	CNOT1
Deadenylation of mRNA	1	439.2×	0.003	CNOT1
M-decay: degradation of maternal mRNAs by maternally stored factors	1	326.3×	0.003	CNOT1

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
positive regulation of cytoplasmic mRNA processing body assembly	1	2407.4×	0.001	CNOT1
negative regulation of retinoic acid receptor signaling pathway	1	1532.0×	0.001	CNOT1
regulation of stem cell population maintenance	1	1404.3×	0.001	CNOT1
miRNA-mediated post-transcriptional gene silencing	1	1296.3×	0.001	CNOT1
positive regulation of nuclear-transcribed mRNA poly(A) tail shortening	1	1296.3×	0.001	CNOT1
positive regulation of mRNA catabolic process	1	1203.7×	0.001	CNOT1
negative regulation of intracellular estrogen receptor signaling pathway	1	1123.5×	0.001	CNOT1
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	1123.5×	0.001	CNOT1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	1053.2×	0.001	CNOT1
trophectodermal cell differentiation	1	991.3×	0.001	CNOT1
nuclear-transcribed mRNA poly(A) tail shortening	1	802.5×	0.001	CNOT1
negative regulation of translation	1	195.9×	0.006	CNOT1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	CNOT1

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
CNOT1	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
CNOT1	3	Binding:3

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	CNOT1

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)
CNOT1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.