Parietal foramina 2

Summary

Parietal foramina 2 (MONDO:0012309) is a disease caused by ALX4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ALX4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 173

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	parietal foramina 2
Mondo ID	MONDO:0012309
MeSH	C566510
OMIM	609597
UMLS	C1865044
MedGen	355358
GARD	0018053
Is cancer (heuristic)	no

Also known as: ALX4 parietal foramina · parietal foramina 2 · parietal foramina caused by mutation in ALX4 · parietal foramina type 2 · PFM2

Data availability: 173 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › neural tube defect › parietal foramina › parietal foramina 2

Related subtypes (2): parietal foramina 1, parietal foramina 3

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

173 retrieved; paginated sample, class counts are floors:

72 uncertain significance, 68 benign, 12 likely benign, 9 pathogenic, 6 benign/likely benign, 3 likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
155902	NM_021926.4(ALX4):c.646C>G (p.Arg216Gly)	ALX4	Pathogenic	no assertion criteria provided
155904	NM_021926.4(ALX4):c.976_985delinsCTAAGATCTCAACAGAGATGGCAACT (p.Asp326fs)	ALX4	Pathogenic	no assertion criteria provided
5013	NM_021926.4(ALX4):c.418C>T (p.Gln140Ter)	ALX4	Pathogenic	no assertion criteria provided
5014	NM_021926.4(ALX4):c.736C>T (p.Gln246Ter)	ALX4	Pathogenic	no assertion criteria provided
5015	NM_021926.4(ALX4):c.653G>A (p.Arg218Gln)	ALX4	Pathogenic	no assertion criteria provided
5016	NM_021926.4(ALX4):c.504del (p.Asp169fs)	ALX4	Pathogenic	no assertion criteria provided
5017	NM_021926.4(ALX4):c.815G>C (p.Arg272Pro)	ALX4	Pathogenic	no assertion criteria provided
5018	NM_021926.4(ALX4):c.620C>A (p.Ser207Ter)	ALX4	Pathogenic	no assertion criteria provided
5019	NM_021926.4(ALX4):c.385_394del (p.Cys129fs)	ALX4	Pathogenic	no assertion criteria provided
1696378	NM_021926.4(ALX4):c.16dup (p.Cys6fs)	ALX4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3257723	NM_021926.4(ALX4):c.1016dup (p.Gly340fs)	ALX4	Likely pathogenic	criteria provided, single submitter
3776156	NM_021926.4(ALX4):c.676del (p.Leu226fs)	ALX4	Likely pathogenic	criteria provided, single submitter
304705	NM_021926.4(ALX4):c.728C>T (p.Ala243Val)	ALX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304714	NM_021926.4(ALX4):c.188G>A (p.Arg63Gln)	ALX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877476	NM_021926.4(ALX4):c.917C>T (p.Pro306Leu)	ALX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304610	NM_021926.4(ALX4):c.*3988T>A	ALX4	Uncertain significance	criteria provided, single submitter
304611	NM_021926.4(ALX4):c.*3825G>C	ALX4	Uncertain significance	criteria provided, single submitter
304615	NM_021926.4(ALX4):c.*3577C>T	ALX4	Uncertain significance	criteria provided, single submitter
304616	NM_021926.4(ALX4):c.*3506T>A	ALX4	Uncertain significance	criteria provided, single submitter
304618	NM_021926.4(ALX4):c.*3382G>A	ALX4	Uncertain significance	criteria provided, single submitter
304619	NM_021926.4(ALX4):c.*3381C>T	ALX4	Uncertain significance	criteria provided, single submitter
304620	NM_021926.4(ALX4):c.*3241C>G	ALX4	Uncertain significance	criteria provided, single submitter
304622	NM_021926.4(ALX4):c.*3112C>T	ALX4	Uncertain significance	criteria provided, single submitter
304625	NM_021926.4(ALX4):c.*3033G>A	ALX4	Uncertain significance	criteria provided, single submitter
304626	NM_021926.4(ALX4):c.*3016G>A	ALX4	Uncertain significance	criteria provided, single submitter
304628	NM_021926.4(ALX4):c.*2991G>A	ALX4	Uncertain significance	criteria provided, multiple submitters, no conflicts
304629	NM_021926.4(ALX4):c.*2883C>A	ALX4	Uncertain significance	criteria provided, single submitter
304630	NM_021926.4(ALX4):c.*2835A>T	ALX4	Uncertain significance	criteria provided, single submitter
304635	NM_021926.4(ALX4):c.*2668T>C	ALX4	Uncertain significance	criteria provided, single submitter
304637	NM_021926.4(ALX4):c.*2489C>T	ALX4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
ALX4	Definitive	Autosomal dominant	parietal foramina 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALX4	Orphanet:228390	Frontonasal dysplasia-alopecia-genital anomalies syndrome
ALX4	Orphanet:35093	Non-syndromic sagittal craniosynostosis
ALX4	Orphanet:52022	Potocki-Shaffer syndrome
ALX4	Orphanet:60015	Enlarged parietal foramina

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
ALX4	HGNC:450	ENSG00000052850	Q9H161	Homeobox protein aristaless-like 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALX4	Homeobox protein aristaless-like 4	Transcription factor involved in skull and limb development.

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALX4	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

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
buccal mucosa cell	1
cranial nerve II	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALX4	82	broad	yes	primordial germ cell in gonad, buccal mucosa cell, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALX4	1,162

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALX4	Q9H161	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
embryonic hindlimb morphogenesis	1	581.1×	0.007	ALX4
digestive tract development	1	526.6×	0.007	ALX4
embryonic forelimb morphogenesis	1	495.6×	0.007	ALX4
embryonic skeletal system morphogenesis	1	391.9×	0.007	ALX4
hair follicle development	1	383.0×	0.007	ALX4
embryonic digit morphogenesis	1	300.9×	0.007	ALX4
neuron development	1	255.3×	0.007	ALX4
roof of mouth development	1	247.8×	0.007	ALX4
post-embryonic development	1	205.5×	0.008	ALX4
anterior/posterior pattern specification	1	181.2×	0.008	ALX4
muscle organ development	1	166.8×	0.008	ALX4
skeletal system development	1	125.8×	0.009	ALX4
regulation of apoptotic process	1	83.4×	0.013	ALX4
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ALX4

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
ALX4	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	ALX4

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)
ALX4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.