Hereditary spastic paraplegia 44

Summary

Hereditary spastic paraplegia 44 (MONDO:0013179) is a disease caused by GJC2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GJC2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000649	Abnormality of visual evoked potentials	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001761	Pes cavus	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0003429	CNS hypomyelination	Very frequent (80-99%)
HP:0006958	Abnormal auditory evoked potentials	Very frequent (80-99%)
HP:0007377	Abnormality of somatosensory evoked potentials	Very frequent (80-99%)
HP:0012896	Abnormal motor evoked potentials	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002839	Urinary bladder sphincter dysfunction	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 44
Mondo ID	MONDO:0013179
MeSH	C567707
OMIM	613206
Orphanet	320401
DOID	DOID:0110796
SNOMED CT	723821002
UMLS	C2750784
MedGen	413042
GARD	0017478
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in GJC2 · GJC2 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 44 · spastic paraplegia 44, autosomal recessive · SPG44

Data availability: 15 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 44

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1363305	NM_020435.4(GJC2):c.1141_1151del (p.Ser381fs)	GJC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2078	NM_020435.4(GJC2):c.108C>G (p.Ile36Met)	GJC2	Pathogenic	criteria provided, single submitter
30759	NM_020435.4(GJC2):c.-167A>G	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
656694	NM_020435.4(GJC2):c.1134_1144del (p.Ala379fs)	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779699	NM_020435.4(GJC2):c.976_992dup (p.Asp332fs)	GJC2	Likely pathogenic	criteria provided, single submitter
930587	NM_020435.4(GJC2):c.550_566del (p.Ala184fs)	GJC2	Likely pathogenic	criteria provided, single submitter
445910	NM_020435.4(GJC2):c.1234C>T (p.His412Tyr)	GJC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2432126	NM_020435.4(GJC2):c.400G>A (p.Gly134Ser)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3251968	NM_020435.4(GJC2):c.184G>C (p.Gly62Arg)	GJC2	Uncertain significance	criteria provided, single submitter
3580792	NM_020435.4(GJC2):c.1162G>C (p.Gly388Arg)	GJC2	Uncertain significance	criteria provided, single submitter
3893127	NM_020435.4(GJC2):c.256G>A (p.Val86Ile)	GJC2	Uncertain significance	criteria provided, single submitter
3896878	NM_020435.4(GJC2):c.14G>T (p.Ser5Ile)	GJC2	Uncertain significance	criteria provided, single submitter
441072	NM_020435.4(GJC2):c.1254_1258delinsCG (p.Lys418_Arg420delinsAsnGly)	GJC2	Uncertain significance	criteria provided, single submitter
943603	NM_020435.4(GJC2):c.436_462del (p.Pro146_Glu154del)	GJC2	Uncertain significance	criteria provided, single submitter
235758	NM_020435.4(GJC2):c.108C>T (p.Ile36=)	GJC2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
GJC2	Strong	Autosomal recessive	hereditary spastic paraplegia 44	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJC2	Orphanet:280282	Pelizaeus-Merzbacher-like disease due to GJC2 mutation
GJC2	Orphanet:320401	Autosomal recessive spastic paraplegia type 44
GJC2	Orphanet:568051	GJC2-related late-onset primary lymphedema

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
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

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)
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS

Expression context

Cohort genes with no expression data: 0.

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
C1 segment of cervical spinal cord	1
inferior vagus X ganglion	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJC2	638

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJC2	Q5T442	68.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Gap junction assembly	1	292.8×	0.003	GJC2

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
cell communication by electrical coupling	1	4213.0×	7e-04	GJC2
response to toxic substance	1	210.7×	0.007	GJC2
cell-cell signaling	1	69.6×	0.014	GJC2

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
GJC2	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	GJC2

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)
GJC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.