Microcephaly 4, primary, autosomal recessive

Summary

Microcephaly 4, primary, autosomal recessive (MONDO:0011437) is a disease caused by KNL1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KNL1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 138

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 4, primary, autosomal recessive
Mondo ID	MONDO:0011437
MeSH	C565792
OMIM	604321
DOID	DOID:0070291
UMLS	C1858516
MedGen	347655
GARD	0015367
Is cancer (heuristic)	no

Also known as: MCPH4 · microcephaly 4, primary, autosomal recessive

Data availability: 138 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 4, 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 3, primary, autosomal recessive, microcephaly 5, 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

138 retrieved; paginated sample, class counts are floors:

79 uncertain significance, 22 conflicting classifications of pathogenicity, 15 benign, 9 benign/likely benign, 7 likely pathogenic, 3 pathogenic, 2 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1690305	NM_144508.5(KNL1):c.1076del (p.Gly359fs)	KNL1	Pathogenic	criteria provided, single submitter
217515	NM_144508.5(KNL1):c.5184dup (p.Ile1729fs)	KNL1	Pathogenic	criteria provided, single submitter
39707	NM_144508.5(KNL1):c.6045G>A (p.Met2015Ile)	KNL1	Pathogenic	criteria provided, single submitter
1684287	NM_144508.5(KNL1):c.2044_2047del (p.Lys681_Gln682insTer)	KNL1	Likely pathogenic	criteria provided, single submitter
210578	NM_144508.5(KNL1):c.694del (p.Asp232fs)	KNL1	Likely pathogenic	criteria provided, single submitter
2441015	NM_144508.5(KNL1):c.197_197+4del	KNL1	Likely pathogenic	criteria provided, single submitter
3779800	NM_144508.5(KNL1):c.4076_4077del (p.Ser1359fs)	KNL1	Likely pathogenic	criteria provided, single submitter
434584	NM_144508.5(KNL1):c.4745_4746delinsC (p.Leu1582fs)	KNL1	Likely pathogenic	criteria provided, single submitter
495234	NM_144508.5(KNL1):c.6349G>T (p.Asp2117Tyr)	KNL1	Likely pathogenic	criteria provided, single submitter
495235	NM_144508.5(KNL1):c.1521A>G (p.Gln507=)	KNL1	Likely pathogenic	criteria provided, single submitter
128584	NM_144508.5(KNL1):c.5631C>T (p.Leu1877=)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128606	NM_144508.5(KNL1):c.6334G>A (p.Val2112Ile)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191054	NM_144508.5(KNL1):c.3634G>A (p.Ala1212Thr)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210571	NM_144508.5(KNL1):c.5271C>T (p.Cys1757=)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210573	NM_144508.5(KNL1):c.5974G>T (p.Ala1992Ser)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210577	NM_144508.5(KNL1):c.6482A>G (p.Asp2161Gly)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315841	NM_144508.5(KNL1):c.75+6A>G	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315844	NM_144508.5(KNL1):c.812C>G (p.Thr271Ser)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315849	NM_144508.5(KNL1):c.1768G>T (p.Ala590Ser)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315857	NM_144508.5(KNL1):c.3573A>G (p.Ile1191Met)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315859	NM_144508.5(KNL1):c.3999C>T (p.Cys1333=)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315864	NM_144508.5(KNL1):c.4619G>A (p.Gly1540Glu)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315869	NM_144508.5(KNL1):c.5538A>G (p.Glu1846=)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315872	NM_144508.5(KNL1):c.6594+10G>A	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420525	NM_144508.5(KNL1):c.4772A>G (p.Asn1591Ser)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
434582	NM_144508.5(KNL1):c.4231G>A (p.Gly1411Arg)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
489318	NM_144508.5(KNL1):c.6416-13T>G	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730228	NM_144508.5(KNL1):c.6043A>C (p.Met2015Leu)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739302	NM_144508.5(KNL1):c.5112C>T (p.Asn1704=)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739413	NM_144508.5(KNL1):c.5064G>C (p.Pro1688=)	KNL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
KNL1	Strong	Autosomal recessive	microcephaly 4, primary, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KNL1	Orphanet:2512	Autosomal recessive primary microcephaly

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
KNL1	HGNC:24054	ENSG00000137812	Q8NG31	Outer kinetochore KNL1 complex subunit KNL1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KNL1	Outer kinetochore KNL1 complex subunit KNL1	Acts as a component of the outer kinetochore KNL1 complex that serves as a docking point for spindle assembly checkpoint components and mediates microtubule-kinetochore interactions.

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)
KNL1	Other/Unknown	no		Blinkin, Knl1_RWD_C, KNL1_MELT_rpt

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
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KNL1	193	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KNL1	3,438

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KNL1	Q8NG31	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Nucleosome assembly	1	475.8×	0.021	KNL1
Chromosome Maintenance	1	211.5×	0.021	KNL1
Amplification of signal from the kinetochores	1	196.9×	0.021	KNL1
Deposition of new CENPA-containing nucleosomes at the centromere	1	158.6×	0.021	KNL1
Mitotic Spindle Checkpoint	1	158.6×	0.021	KNL1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	116.5×	0.021	KNL1
Mitotic Metaphase and Anaphase	1	96.8×	0.021	KNL1
Mitotic Anaphase	1	96.8×	0.021	KNL1
EML4 and NUDC in mitotic spindle formation	1	92.8×	0.021	KNL1
Cell Cycle Checkpoints	1	88.5×	0.021	KNL1
Resolution of Sister Chromatid Cohesion	1	86.5×	0.021	KNL1
RHO GTPases Activate Formins	1	77.7×	0.021	KNL1
Mitotic Prometaphase	1	69.2×	0.021	KNL1
RHO GTPase Effectors	1	68.0×	0.021	KNL1
M Phase	1	66.0×	0.021	KNL1
Separation of Sister Chromatids	1	60.7×	0.022	KNL1
Cell Cycle, Mitotic	1	48.2×	0.026	KNL1
Cell Cycle	1	36.0×	0.031	KNL1
Signaling by Rho GTPases	1	34.2×	0.031	KNL1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.031	KNL1
Signal Transduction	1	10.2×	0.098	KNL1

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
positive regulation of meiosis I spindle assembly checkpoint	1	16852.0×	5e-04	KNL1
homologous chromosome orientation in meiotic metaphase I	1	8426.0×	5e-04	KNL1
regulation of mitotic cell cycle spindle assembly checkpoint	1	2106.5×	0.001	KNL1
protein localization to kinetochore	1	1404.3×	0.001	KNL1
attachment of spindle microtubules to kinetochore	1	936.2×	0.002	KNL1
mitotic sister chromatid segregation	1	481.5×	0.003	KNL1
acrosome assembly	1	455.5×	0.003	KNL1
cell division	1	46.2×	0.022	KNL1

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
KNL1	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	KNL1

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)
KNL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.