Hyperekplexia 4

Summary

Hyperekplexia 4 (MONDO:0044330) is a disease caused by ATAD1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ATAD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperekplexia 4
Mondo ID	MONDO:0044330
OMIM	618011
DOID	DOID:0080581
UMLS	C4693933
MedGen	1642659
GARD	0016284
Is cancer (heuristic)	no

Also known as: HKPX4 · hyperekplexia 4

Data availability: 10 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › hyperekplexia › hereditary hyperekplexia › hyperekplexia 4

Related subtypes (4): hyperekplexia 1, developmental and epileptic encephalopathy, 8, hyperekplexia 3, hyperekplexia 2

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

10 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
545495	NM_001321967.2(ATAD1):c.826G>T (p.Glu276Ter)	ATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545496	NM_001321967.2(ATAD1):c.1070_1071del (p.His357fs)	ATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338448	GRCh37/hg19 10q23.31(chr10:89549991-89550223)x0	ATAD1	Likely pathogenic	no assertion criteria provided
1364221	NM_001321967.2(ATAD1):c.121A>G (p.Ile41Val)	ATAD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1496458	NM_001321967.2(ATAD1):c.767A>T (p.His256Leu)	ATAD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2062032	NM_001321967.2(ATAD1):c.160C>G (p.Gln54Glu)	ATAD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3598496	NM_001321967.2(ATAD1):c.-48C>G	ATAD1	Uncertain significance	criteria provided, single submitter
4291950	NM_001321967.2(ATAD1):c.418A>G (p.Thr140Ala)	ATAD1	Uncertain significance	criteria provided, single submitter
545497	NM_001321967.2(ATAD1):c.162G>C (p.Gln54His)	ATAD1	Uncertain significance	criteria provided, single submitter
1601366	NM_001321967.2(ATAD1):c.657C>G (p.Leu219=)	ATAD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ATAD1	Strong	Autosomal recessive	hyperekplexia 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATAD1	Orphanet:3197	Hereditary hyperekplexia

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
ATAD1	HGNC:25903	ENSG00000138138	Q8NBU5	Outer mitochondrial transmembrane helix translocase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATAD1	Outer mitochondrial transmembrane helix translocase	Outer mitochondrial translocase required to remove mislocalized tail-anchored transmembrane proteins on mitochondria.

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)
ATAD1	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

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
islet of Langerhans	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATAD1	252	ubiquitous	marker	right testis, left testis, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATAD1	3,099

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATAD1	Q8NBU5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Class I peroxisomal membrane protein import	1	519.1×	0.004	ATAD1
Protein localization	1	190.3×	0.005	ATAD1

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
extraction of mislocalized protein from mitochondrial outer membrane	1	16852.0×	4e-04	ATAD1
negative regulation of synaptic transmission, glutamatergic	1	1685.2×	0.002	ATAD1
positive regulation of receptor internalization	1	702.2×	0.002	ATAD1
regulation of postsynaptic neurotransmitter receptor internalization	1	624.1×	0.002	ATAD1
learning	1	280.9×	0.004	ATAD1
memory	1	183.2×	0.005	ATAD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATAD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	ATAD1

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)
ATAD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.