Microcephaly 5, primary, autosomal recessive

Summary

Microcephaly 5, primary, autosomal recessive (MONDO:0012106) is a disease caused by ASPM (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ASPM (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 712

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 5, primary, autosomal recessive
Mondo ID	MONDO:0012106
MeSH	C563871
OMIM	608716
DOID	DOID:0070280
UMLS	C1837501
MedGen	373344
GARD	0015441
Is cancer (heuristic)	no

Also known as: ASPM autosomal recessive primary microcephaly · autosomal recessive primary microcephaly caused by mutation in ASPM · MCPH5 · microcephaly 5, primary, autosomal recessive

Data availability: 712 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive primary microcephaly › microcephaly 5, primary, autosomal recessive

Related subtypes (28): microcephaly 1, primary, autosomal recessive, microcephaly with simplified gyral pattern, microcephaly 2, primary, autosomal recessive, with or without cortical malformations, microcephaly 4, primary, autosomal recessive, microcephaly 3, primary, autosomal recessive, microcephaly 7, primary, autosomal recessive, microcephaly 8, primary, autosomal recessive, microcephaly 9, primary, autosomal recessive, microcephalic primordial dwarfism due to ZNF335 deficiency, microcephaly 11, primary, autosomal recessive, microcephaly 13, primary, autosomal recessive, microcephaly 12, primary, autosomal recessive, microcephaly 14, primary, autosomal recessive, microcephaly 15, primary, autosomal recessive, microcephaly 16, primary, autosomal recessive, microcephaly 17, primary, autosomal recessive, microcephaly 28, primary, autosomal recessive, microcephaly 29, primary, autosomal recessive, microcephaly 24, primary, autosomal recessive, microcephaly 25, primary, autosomal recessive, microcephaly 19, primary, autosomal recessive, microcephaly 20, primary, autosomal recessive, microcephaly 21, primary, autosomal recessive, microcephaly 22, primary, autosomal recessive, microcephaly 23, primary, autosomal recessive, microcephaly with or without short stature, microcephaly 30, primary, autosomal recessive, microcephaly 31, primary, 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

600 retrieved; paginated sample, class counts are floors:

191 uncertain significance, 126 pathogenic, 102 conflicting classifications of pathogenicity, 43 likely pathogenic, 38 benign/likely benign, 34 not provided, 26 benign, 22 pathogenic/likely pathogenic, 18 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3897899	NM_018136.5:c.[8195_8198delGAAA];[4768C>T]		Pathogenic	criteria provided, single submitter
424707	NM_018136.4(ASPM):c.[10168C>T];[8098C>T]		Pathogenic	no assertion criteria provided
1012239	NM_018136.5(ASPM):c.1789C>T (p.Arg597Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1029675	NM_018136.5(ASPM):c.6994C>T (p.Arg2332Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1029677	NM_018136.5(ASPM):c.9286C>T (p.Arg3096Ter)	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029678	NM_018136.5(ASPM):c.9659G>A (p.Trp3220Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1180742	NM_018136.5(ASPM):c.1592_1595del (p.Val531fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1279935	NM_018136.5(ASPM):c.8141del (p.Ala2714fs)	ASPM	Pathogenic	criteria provided, single submitter
1320079	NM_018136.5(ASPM):c.2760+1G>A	ASPM	Pathogenic	criteria provided, single submitter
1320080	NM_018136.5(ASPM):c.9641T>A (p.Leu3214Ter)	ASPM	Pathogenic	criteria provided, single submitter
1323512	NM_018136.5(ASPM):c.2581dup (p.Ile861fs)	ASPM	Pathogenic	criteria provided, single submitter
1323515	NM_018136.5(ASPM):c.4451_4455del (p.Tyr1484fs)	ASPM	Pathogenic	criteria provided, single submitter
1323525	NM_018136.5(ASPM):c.9874C>T (p.Gln3292Ter)	ASPM	Pathogenic	criteria provided, single submitter
1323530	NM_018136.5(ASPM):c.434del (p.Lys145fs)	ASPM	Pathogenic	criteria provided, single submitter
1338429	NM_018136.5(ASPM):c.4612C>T (p.Arg1538Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1339592	NM_018136.5(ASPM):c.10055_10056insGG (p.Ile3352fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1454430	NM_018136.5(ASPM):c.6854_6855del (p.Leu2285fs)	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456095	NM_018136.5(ASPM):c.4707C>A (p.Tyr1569Ter)	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157773	NM_018136.5(ASPM):c.10168C>T (p.Arg3390Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
157777	NM_018136.5(ASPM):c.1138C>T (p.Gln380Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
157778	NM_018136.5(ASPM):c.117_118del (p.Leu41fs)	ASPM	Pathogenic	criteria provided, single submitter
157783	NM_018136.5(ASPM):c.1671_1672del (p.Ser557fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
157785	NM_018136.5(ASPM):c.1726_1729del (p.Lys576fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
157795	NM_018136.5(ASPM):c.2419+2T>C	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157797	NM_018136.5(ASPM):c.2791C>T (p.Arg931Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
157799	NM_018136.5(ASPM):c.2968del (p.Asp990fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
157803	NM_018136.5(ASPM):c.3327T>G (p.Tyr1109Ter)	ASPM	Pathogenic	criteria provided, single submitter
157812	NM_018136.5(ASPM):c.3830G>A (p.Trp1277Ter)	ASPM	Pathogenic	criteria provided, single submitter
157813	NM_018136.5(ASPM):c.3853_3854del (p.Asp1285fs)	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157815	NM_018136.5(ASPM):c.3945_3946del (p.Arg1315fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
ASPM	Definitive	Autosomal recessive	autosomal recessive primary microcephaly	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASPM	Orphanet:2512	Autosomal recessive primary microcephaly
MFSD8	Orphanet:1872	Cone rod dystrophy
MFSD8	Orphanet:228366	CLN7 disease
SLC26A4	Orphanet:705	Pendred syndrome
SLC26A4	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC26A4	Orphanet:95713	Athyreosis
SLC26A4	Orphanet:95720	Thyroid hypoplasia

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
ASPM	HGNC:19048	ENSG00000066279	Q8IZT6	Abnormal spindle-like microcephaly-associated protein	gencc,clinvar
MFSD8	HGNC:28486	ENSG00000164073	Q8NHS3	Major facilitator superfamily domain-containing protein 8	clinvar
SLC26A4	HGNC:8818	ENSG00000091137	O43511	Pendrin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASPM	Abnormal spindle-like microcephaly-associated protein	Involved in mitotic spindle regulation and coordination of mitotic processes.
MFSD8	Major facilitator superfamily domain-containing protein 8	Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function.
SLC26A4	Pendrin	Sodium-independent transporter of chloride and iodide.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	2	51.9×	1e-03
Antibody/Immunoglobulin	1	9.7×	0.099

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASPM	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, CH_dom, ARM-like
MFSD8	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
SLC26A4	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom

Expression context

Cohort genes with no expression data: 0.

3 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
oocyte	1
secondary oocyte	1
ventricular zone	1
adrenal tissue	1
calcaneal tendon	1
oviduct epithelium	1
palpebral conjunctiva	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASPM	176	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte
MFSD8	256	ubiquitous	marker	oviduct epithelium, adrenal tissue, calcaneal tendon
SLC26A4	190	tissue_specific	marker	palpebral conjunctiva, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASPM	2,949
SLC26A4	1,648
MFSD8	1,405

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MFSD8	Q8NHS3	83.20
SLC26A4	O43511	82.72
ASPM	Q8IZT6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
Defective SLC26A4 causes Pendred syndrome (PDS)	1	11420.0×	7e-04	SLC26A4
Inorganic anion exchange by SLC26 transporters	1	1268.9×	0.003	SLC26A4
SLC transporter disorders	1	203.9×	0.012	SLC26A4
Disorders of transmembrane transporters	1	139.3×	0.012	SLC26A4
R-HSA-425393	1	129.8×	0.012	SLC26A4
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC26A4
Transport of small molecules	1	25.1×	0.045	SLC26A4
Disease	1	13.1×	0.076	SLC26A4

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
negative regulation of asymmetric cell division	1	5617.3×	0.003	ASPM
maintenance of location	1	5617.3×	0.003	MFSD8
glycolipid metabolic process	1	2808.7×	0.003	MFSD8
forebrain neuroblast division	1	2808.7×	0.003	ASPM
inclusion body assembly	1	2808.7×	0.003	MFSD8
inorganic anion transport	1	1872.4×	0.003	SLC26A4
meiotic spindle assembly	1	1872.4×	0.003	ASPM
regulation of lysosomal protein catabolic process	1	1872.4×	0.003	MFSD8
spindle localization	1	1123.5×	0.005	ASPM
maintenance of centrosome location	1	936.2×	0.005	ASPM
asymmetric cell division	1	802.5×	0.005	ASPM
iodide transport	1	802.5×	0.005	SLC26A4
microglia differentiation	1	510.7×	0.008	MFSD8
regulation of pH	1	468.1×	0.008	SLC26A4
sulfate transmembrane transport	1	401.2×	0.008	SLC26A4
glycoprotein metabolic process	1	374.5×	0.009	MFSD8
lysosomal protein catabolic process	1	351.1×	0.009	MFSD8
spindle organization	1	330.4×	0.009	ASPM
TORC1 signaling	1	267.5×	0.009	MFSD8
astrocyte differentiation	1	255.3×	0.009	MFSD8
regulation of meiotic cell cycle	1	255.3×	0.009	ASPM
developmental growth	1	244.2×	0.009	ASPM
neuronal stem cell population maintenance	1	224.7×	0.010	ASPM
positive regulation of neuroblast proliferation	1	193.7×	0.011	ASPM
motor behavior	1	187.2×	0.011	MFSD8
neuromuscular process	1	175.5×	0.011	MFSD8
reactive oxygen species metabolic process	1	156.0×	0.012	MFSD8
determination of adult lifespan	1	144.0×	0.013	MFSD8
glycolytic process	1	127.7×	0.013	MFSD8
oogenesis	1	127.7×	0.013	ASPM

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
ASPM	0	0
MFSD8	0	0
SLC26A4	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
SLC26A4	37	Binding:37

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	0
D	Druggable family + AlphaFold only, no drug	3	ASPM, MFSD8, SLC26A4
E	Difficult family or no structure, no drug	0

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)
ASPM	0	—
MFSD8	0	—
SLC26A4	37	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.