Neutropenia, severe congenital, 11, autosomal dominant

Summary

Neutropenia, severe congenital, 11, autosomal dominant (MONDO:0958017) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neutropenia, severe congenital, 11, autosomal dominant
Mondo ID	MONDO:0958017
OMIM	620674
UMLS	C5882742
MedGen	1846394
GARD	0026911
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › severe congenital neutropenia › neutropenia, severe congenital, 11, autosomal dominant

Related subtypes (7): autosomal dominant severe congenital neutropenia, X-linked severe congenital neutropenia, autosomal recessive severe congenital neutropenia, neutropenia, severe congenital, 9, autosomal dominant, neutropenia, severe congenital, 8, autosomal dominant, neutropenia, severe congenital, 10, autosomal recessive, neutropenia, severe congenital, 12, autosomal recessive

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

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2686029	NM_013336.4(SEC61A1):c.275A>G (p.Gln92Arg)	SEC61A1	Pathogenic	no assertion criteria provided
3159380	NM_013336.4(SEC61A1):c.1060G>A (p.Val354Met)	RUVBL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3588360	NM_013336.4(SEC61A1):c.1075G>A (p.Val359Ile)	RUVBL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEC61A1	Orphanet:697417	Common variable immunodeficiency phenotype due to SEC61A1 deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RUVBL1	HGNC:10474	ENSG00000175792	Q9Y265	RuvB-like 1	clinvar
SEC61A1	HGNC:18276	ENSG00000058262	P61619	Protein transport protein Sec61 subunit alpha isoform 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RUVBL1	RuvB-like 1	Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3’ to 5’) activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activ…
SEC61A1	Protein transport protein Sec61 subunit alpha isoform 1	Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RUVBL1	Other/Unknown	no		AAA+_ATPase, TIP49_P-loop, RuvB-like
SEC61A1	Other/Unknown	no		SecY/SEC61-alpha, Translocon_Sec61/SecY_plug_dom, SecY_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	1
right uterine tube	1
ventricular zone	1
body of pancreas	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RUVBL1	134	ubiquitous	marker	right uterine tube, ventricular zone, primordial germ cell in gonad
SEC61A1	284	ubiquitous	marker	body of pancreas, stromal cell of endometrium, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RUVBL1	1,549
SEC61A1	490

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RUVBL1	Q9Y265	36
SEC61A1	P61619	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Extension of Telomeres	1	300.5×	0.023	RUVBL1
Nucleosome assembly	1	237.9×	0.023	RUVBL1
Telomere Extension By Telomerase	1	228.4×	0.023	RUVBL1
Global Genome Nucleotide Excision Repair (GG-NER)	1	228.4×	0.023	RUVBL1
Telomere Maintenance	1	184.2×	0.023	RUVBL1
Antigen processing-Cross presentation	1	158.6×	0.023	SEC61A1
DNA Damage Recognition in GG-NER	1	142.8×	0.023	RUVBL1
Nucleotide Excision Repair	1	142.8×	0.023	RUVBL1
Metabolism of proteins	2	12.4×	0.023	RUVBL1, SEC61A1
Chromosome Maintenance	1	105.7×	0.028	RUVBL1
Deposition of new CENPA-containing nucleosomes at the centromere	1	79.3×	0.031	RUVBL1
ER-Phagosome pathway	1	64.9×	0.031	SEC61A1
Deubiquitination	1	62.1×	0.031	RUVBL1
UCH proteinases	1	62.1×	0.031	RUVBL1
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.031	RUVBL1
TCF dependent signaling in response to WNT	1	58.9×	0.031	RUVBL1
Signaling by WNT	1	56.0×	0.031	RUVBL1
SRP-dependent cotranslational protein targeting to membrane	1	50.1×	0.032	SEC61A1
DNA Repair	1	49.2×	0.032	RUVBL1
Chromatin organization	1	40.8×	0.036	RUVBL1
HATs acetylate histones	1	39.6×	0.036	RUVBL1
Chromatin modifying enzymes	1	36.1×	0.037	RUVBL1
Class I MHC mediated antigen processing & presentation	1	35.0×	0.037	SEC61A1
Translation	1	31.0×	0.040	SEC61A1
Ub-specific processing proteases	1	26.6×	0.045	RUVBL1
Cell Cycle	1	18.0×	0.063	RUVBL1
Adaptive Immune System	1	14.9×	0.073	SEC61A1
Post-translational protein modification	1	9.6×	0.109	RUVBL1
Immune System	1	6.5×	0.153	SEC61A1
Signal Transduction	1	5.1×	0.187	RUVBL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pronephric nephron development	1	8426.0×	0.004	SEC61A1
telomerase RNA localization to Cajal body	1	1203.7×	0.005	RUVBL1
SRP-dependent cotranslational protein targeting to membrane	1	1053.2×	0.005	SEC61A1
SRP-dependent cotranslational protein targeting to membrane, translocation	1	1053.2×	0.005	SEC61A1
post-translational protein targeting to membrane, translocation	1	1053.2×	0.005	SEC61A1
box C/D snoRNP assembly	1	842.6×	0.005	RUVBL1
cotranslational protein targeting to membrane	1	842.6×	0.005	SEC61A1
protein insertion into ER membrane	1	766.0×	0.005	SEC61A1
post-translational protein targeting to endoplasmic reticulum membrane	1	702.2×	0.005	SEC61A1
protein targeting to ER	1	561.7×	0.005	SEC61A1
positive regulation of telomere maintenance in response to DNA damage	1	561.7×	0.005	RUVBL1
regulation of DNA strand elongation	1	526.6×	0.005	RUVBL1
regulation of chromosome organization	1	468.1×	0.006	RUVBL1
regulation of double-strand break repair	1	290.6×	0.008	RUVBL1
response to type II interferon	1	263.3×	0.009	SEC61A1
endoplasmic reticulum organization	1	210.7×	0.010	SEC61A1
positive regulation of double-strand break repair via homologous recombination	1	191.5×	0.010	RUVBL1
regulation of DNA replication	1	183.2×	0.010	RUVBL1
positive regulation of DNA repair	1	179.3×	0.010	RUVBL1
DNA recombination	1	168.5×	0.010	RUVBL1
regulation of embryonic development	1	165.2×	0.010	RUVBL1
regulation of DNA repair	1	138.1×	0.011	RUVBL1
telomere maintenance	1	133.8×	0.011	RUVBL1
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.018	RUVBL1
regulation of apoptotic process	1	41.7×	0.032	RUVBL1
regulation of cell cycle	1	37.3×	0.034	RUVBL1
chromatin remodeling	1	36.5×	0.034	RUVBL1
protein stabilization	1	33.4×	0.036	RUVBL1
DNA repair	1	31.9×	0.036	RUVBL1
cell division	1	23.1×	0.049	RUVBL1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
RUVBL1	1	2
SEC61A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RUVBL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RUVBL1	15	Binding:15
SEC61A1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	RUVBL1

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	1	RUVBL1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SEC61A1

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)
SEC61A1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.