pontocerebellar hypoplasia type 2D

Summary

pontocerebellar hypoplasia type 2D (MONDO:0013438) is a disease caused by SEPSECS (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SEPSECS (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 206

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 2D
Mondo ID	MONDO:0013438
OMIM	613811
DOID	DOID:0060270
UMLS	C3151140
MedGen	462490
GARD	0015717
Is cancer (heuristic)	no

Also known as: non-syndromic pontocerebellar hypoplasia caused by mutation in SEPSECS · PCH2D · pontocerebellar hypoplasia type 2D · pontocerebellar hypoplasia, type 2D · SEPSECS non-syndromic pontocerebellar hypoplasia

Data availability: 206 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › bulbospinal muscular atrophy › pontocerebellar hypoplasia type 2 › pontocerebellar hypoplasia type 2D

Related subtypes (4): pontocerebellar hypoplasia type 2A, pontocerebellar hypoplasia type 2B, pontocerebellar hypoplasia type 2C, pontocerebellar hypoplasia, type 2F

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

206 retrieved; paginated sample, class counts are floors:

94 uncertain significance, 34 likely pathogenic, 21 pathogenic/likely pathogenic, 16 likely benign, 16 conflicting classifications of pathogenicity, 15 benign, 5 pathogenic, 4 benign/likely benign, 1 vus-mid

ClinVar	Variant (HGVS)	Gene	Classification	Review
984624	NM_016955.4(SEPSECS):c.114+3A>G	LOC129992330	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203880	NM_000282.4(PCCA):c.425G>A (p.Gly142Asp)	PCCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069394	NM_016955.4(SEPSECS):c.835del (p.Val279fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070527	NM_016955.4(SEPSECS):c.448_449del (p.Leu150fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071583	NM_016955.4(SEPSECS):c.313C>T (p.Gln105Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072606	NM_016955.4(SEPSECS):c.466C>T (p.Arg156Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072923	NM_016955.4(SEPSECS):c.1148dup (p.His383fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075426	NM_016955.4(SEPSECS):c.811C>T (p.Arg271Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298330	NM_016955.4(SEPSECS):c.1A>T (p.Met1Leu)	SEPSECS	Pathogenic	criteria provided, single submitter
1356091	NM_016955.4(SEPSECS):c.1023_1026del (p.Glu343fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1379888	NM_016955.4(SEPSECS):c.482del (p.Lys161fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1424843	NM_016955.4(SEPSECS):c.1178C>A (p.Ser393Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1434019	NM_016955.4(SEPSECS):c.1169_1173del (p.Gln390fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18400	NM_016955.4(SEPSECS):c.1001A>G (p.Tyr334Cys)	SEPSECS	Pathogenic	criteria provided, multiple submitters, no conflicts
18401	NM_016955.4(SEPSECS):c.715G>A (p.Ala239Thr)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2126148	NM_016955.4(SEPSECS):c.505C>T (p.Arg169Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2416280	NM_016955.4(SEPSECS):c.919del (p.Ser307fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279890	NM_016955.5(SEPSECS):c.808dup	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3004656	NM_016955.4(SEPSECS):c.163_164del (p.Leu55fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081793	NM_016955.4(SEPSECS):c.568G>T (p.Glu190Ter)	SEPSECS	Pathogenic	criteria provided, single submitter
4081794	NM_016955.4(SEPSECS):c.51C>G (p.Tyr17Ter)	SEPSECS	Pathogenic	criteria provided, single submitter
4081795	NM_016955.4(SEPSECS):c.672_675del (p.Ser225fs)	SEPSECS	Pathogenic	criteria provided, single submitter
522119	NM_016955.4(SEPSECS):c.612dup (p.Val205fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645393	NM_016955.4(SEPSECS):c.289C>T (p.Arg97Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
851642	NM_016955.4(SEPSECS):c.449dup (p.Cys151fs)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
953846	NM_016955.4(SEPSECS):c.41C>A (p.Ser14Ter)	SEPSECS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4061266	NM_016955.4(SEPSECS):c.97del (p.Arg33fs)	LOC129992330	Likely pathogenic	criteria provided, single submitter
1066471	NM_016955.4(SEPSECS):c.389-1G>A	SEPSECS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1472579	NM_016955.4(SEPSECS):c.389-13_404del	SEPSECS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3005390	NM_016955.4(SEPSECS):c.547+1G>C	SEPSECS	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 6 · 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
SEPSECS	Definitive	Autosomal recessive	pontocerebellar hypoplasia type 2D	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2
CLN5	Orphanet:699802	Late infantile CLN5 disease
CLN5	Orphanet:699807	Juvenile CLN5 disease
CLN5	Orphanet:699812	Adult CLN5 disease
PCCA	Orphanet:35	Propionic acidemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	gencc,clinvar
CLN5	HGNC:2076	ENSG00000102805	O75503	Bis(monoacylglycero)phosphate synthase CLN5	clinvar
PCCA	HGNC:8653	ENSG00000175198	P05165	Propionyl-CoA carboxylase alpha chain, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
CLN5	Bis(monoacylglycero)phosphate synthase CLN5	Catalyzes the synthesis of bis(monoacylglycero)phosphate (BMP) via transacylation of 2 molecules of lysophosphatidylglycerol (LPG).
PCCA	Propionyl-CoA carboxylase alpha chain, mitochondrial	This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
CLN5	Other/Unknown	no		CLN5
PCCA	Enzyme (other)	yes	6.4.1.3	Biotin_lipoyl, Biotin_BS, CPAse_ATP-bd

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
ileal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
corpus epididymis	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver
CLN5	271	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
PCCA	289	ubiquitous	marker	right lobe of liver, corpus epididymis, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCCA	2,036
SEPSECS	1,756
CLN5	1,033

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCCA	P05165	25
SEPSECS	Q9HD40	7
CLN5	O75503	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Propionyl-CoA catabolism	1	1142.0×	0.004	PCCA
Defective HLCS causes multiple carboxylase deficiency	1	815.7×	0.004	PCCA
Biotin transport and metabolism	1	519.1×	0.004	PCCA
Selenoamino acid metabolism	1	98.5×	0.018	SEPSECS
Selenocysteine synthesis	1	60.1×	0.023	SEPSECS
Metabolism of amino acids and derivatives	1	33.8×	0.034	SEPSECS
Metabolism	1	5.8×	0.165	SEPSECS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 GTP binding	1	5617.3×	0.002	CLN5
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	2808.7×	0.002	SEPSECS
branched-chain amino acid metabolic process	1	1872.4×	0.002	PCCA
short-chain fatty acid catabolic process	1	1872.4×	0.002	PCCA
selenocysteine incorporation	1	624.1×	0.005	SEPSECS
obsolete signal peptide processing	1	468.1×	0.005	CLN5
neuron maturation	1	267.5×	0.008	CLN5
lysosomal lumen acidification	1	224.7×	0.008	CLN5
lysosome organization	1	102.1×	0.016	CLN5
protein catabolic process	1	79.1×	0.018	CLN5
neurogenesis	1	69.3×	0.018	CLN5
retrograde transport, endosome to Golgi	1	68.5×	0.018	CLN5
fatty acid metabolic process	1	64.6×	0.018	PCCA
brain development	1	26.5×	0.037	CLN5
visual perception	1	26.5×	0.037	CLN5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SEPSECS	0	0
CLN5	0	0
PCCA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PCCA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase
PCCA	6.4.1.3	propionyl-CoA carboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	SEPSECS, PCCA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLN5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SEPSECS	0	—
CLN5	0	—
PCCA	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.