Microcephaly 16, primary, autosomal recessive

Summary

Microcephaly 16, primary, autosomal recessive (MONDO:0014730) is a disease caused by ANKLE2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ANKLE2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 16, primary, autosomal recessive
Mondo ID	MONDO:0014730
OMIM	616681
DOID	DOID:0070289
UMLS	C4225249
MedGen	898705
GARD	0016151
Is cancer (heuristic)	no

Also known as: MCPH16 · microcephaly 16, primary, autosomal recessive · microcephaly 16, primary, autosomal recessive; MCPH16

Data availability: 31 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 16, 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 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 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

31 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 10 benign, 4 likely pathogenic, 4 pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2443910	NM_015114.3(ANKLE2):c.706C>T (p.Arg236Ter)	ANKLE2	Pathogenic	no assertion criteria provided
2443912	NM_015114.3(ANKLE2):c.1891+1701_2615+14delinsA	ANKLE2	Pathogenic	no assertion criteria provided
3339785	NC_000012.11:g.(133319863_133324417)(133338419?)del	ANKLE2	Pathogenic	criteria provided, single submitter
930179	NM_015114.3(ANKLE2):c.1870C>T (p.Arg624Ter)	ANKLE2	Pathogenic	criteria provided, multiple submitters, no conflicts
218246	NM_015114.3(ANKLE2):c.1717C>G (p.Leu573Val)	ANKLE2	Likely pathogenic	criteria provided, single submitter
3254693	NM_015114.3(ANKLE2):c.2495C>G (p.Ser832Ter)	ANKLE2	Likely pathogenic	criteria provided, single submitter
4845688	NM_015114.3(ANKLE2):c.1508_1518del (p.Ala503fs)	ANKLE2	Likely pathogenic	criteria provided, single submitter
635194	NM_015114.3(ANKLE2):c.601G>T (p.Gly201Trp)	ANKLE2	Likely pathogenic	criteria provided, single submitter
218245	NM_015114.3(ANKLE2):c.2344C>T (p.Gln782Ter)	ANKLE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802911	NM_015114.3(ANKLE2):c.1892-127_1892-65del	ANKLE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806973	NM_015114.3(ANKLE2):c.19G>A (p.Ala7Thr)	ANKLE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030463	NM_015114.3(ANKLE2):c.2467C>T (p.Arg823Trp)	ANKLE2	Uncertain significance	criteria provided, single submitter
1312496	NM_015114.3(ANKLE2):c.1202A>G (p.Asp401Gly)	ANKLE2	Uncertain significance	criteria provided, single submitter
3064430	NM_015114.3(ANKLE2):c.473G>T (p.Gly158Val)	ANKLE2	Uncertain significance	criteria provided, single submitter
3235059	NM_015114.3(ANKLE2):c.1184G>A (p.Arg395His)	ANKLE2	Uncertain significance	criteria provided, single submitter
3235060	NM_015114.3(ANKLE2):c.997C>T (p.Pro333Ser)	ANKLE2	Uncertain significance	criteria provided, single submitter
3778767	NM_015114.3(ANKLE2):c.7_22dup (p.Ala8fs)	ANKLE2	Uncertain significance	criteria provided, single submitter
4292837	NM_015114.3(ANKLE2):c.913C>T (p.Arg305Cys)	ANKLE2	Uncertain significance	criteria provided, single submitter
548479	NM_015114.3(ANKLE2):c.1060G>A (p.Val354Met)	ANKLE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
560228	NM_015114.3(ANKLE2):c.1687G>A (p.Glu563Lys)	ANKLE2	Uncertain significance	criteria provided, single submitter
978453	NM_015114.3(ANKLE2):c.1606C>T (p.Arg536Cys)	ANKLE2	Uncertain significance	criteria provided, single submitter
1098724	NM_015114.3(ANKLE2):c.2672G>C (p.Gly891Ala)	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1098725	NM_015114.3(ANKLE2):c.2038G>A (p.Glu680Lys)	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192433	NM_015114.3(ANKLE2):c.2159G>A (p.Arg720His)	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192434	NM_015114.3(ANKLE2):c.1891+84G>A	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192435	NM_015114.3(ANKLE2):c.1700+104G>C	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192436	NM_015114.3(ANKLE2):c.1700+48A>G	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192437	NM_015114.3(ANKLE2):c.1594-93A>G	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192438	NM_015114.3(ANKLE2):c.1421-138G>C	ANKLE2	Benign	criteria provided, multiple submitters, no conflicts
1192467	NM_015114.3(ANKLE2):c.641-35T>A	ANKLE2	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
ANKLE2	Strong	Autosomal recessive	microcephaly 16, primary, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKLE2	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
ANKLE2	HGNC:29101	ENSG00000176915	Q86XL3	Ankyrin repeat and LEM domain-containing protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANKLE2	Ankyrin repeat and LEM domain-containing protein 2	Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKLE2	Scaffold/PPI	no		Ankyrin_rpt, LEM_dom, LEM/LEM-like_dom_sf

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
left testis	1
right testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKLE2	289	ubiquitous	marker	stromal cell of endometrium, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANKLE2	1,917

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKLE2	Q86XL3	65.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.022	ANKLE2
Nuclear Envelope (NE) Reassembly	1	292.8×	0.022	ANKLE2
RHOG GTPase cycle	1	148.3×	0.022	ANKLE2
RAC2 GTPase cycle	1	126.9×	0.022	ANKLE2
Mitotic Metaphase and Anaphase	1	96.8×	0.022	ANKLE2
Mitotic Anaphase	1	96.8×	0.022	ANKLE2
M Phase	1	66.0×	0.027	ANKLE2
RHO GTPase cycle	1	60.1×	0.027	ANKLE2
Cell Cycle, Mitotic	1	48.2×	0.030	ANKLE2
Cell Cycle	1	36.0×	0.032	ANKLE2
Signaling by Rho GTPases	1	34.2×	0.032	ANKLE2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.032	ANKLE2
Signal Transduction	1	10.2×	0.098	ANKLE2

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
regulation of catalytic activity	1	3370.4×	0.001	ANKLE2
negative regulation of phosphorylation	1	2808.7×	0.001	ANKLE2
mitotic nuclear membrane reassembly	1	1685.2×	0.001	ANKLE2
central nervous system development	1	115.4×	0.013	ANKLE2
cell division	1	46.2×	0.026	ANKLE2
negative regulation of apoptotic process	1	34.8×	0.029	ANKLE2

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
ANKLE2	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	ANKLE2

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)
ANKLE2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.