atelosteogenesis type III

Summary

atelosteogenesis type III (MONDO:0007168) is a disease caused by FLNB (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FLNB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 57
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0031095	Abnormal humerus morphology	Frequent (30-79%)
HP:0001248	Short tubular bones of the hand	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002827	Hip dislocation	Frequent (30-79%)
HP:0002999	Patellar dislocation	Frequent (30-79%)
HP:0003042	Elbow dislocation	Frequent (30-79%)
HP:0003417	Coronal cleft vertebrae	Frequent (30-79%)
HP:0004976	Knee dislocation	Frequent (30-79%)
HP:0006408	Distal tapering femur	Frequent (30-79%)
HP:0008417	Vertebral hypoplasia	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0001188	Hand clenching	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0002990	Fibular aplasia	Occasional (5-29%)
HP:0003049	Ulnar deviation of the wrist	Occasional (5-29%)
HP:0003862	Absent humerus	Occasional (5-29%)
HP:0003902	Epiphyseal stippling of the humerus	Occasional (5-29%)
HP:0003974	Absent radius	Occasional (5-29%)
HP:0005257	Thoracic hypoplasia	Occasional (5-29%)
HP:0005619	Thoracolumbar kyphosis	Occasional (5-29%)
HP:0005736	Short tibia	Occasional (5-29%)
HP:0005905	Abnormal cervical curvature	Occasional (5-29%)
HP:0006384	Club-shaped distal femur	Occasional (5-29%)
HP:0008755	Laryngotracheomalacia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	atelosteogenesis type III
Mondo ID	MONDO:0007168
MeSH	C579928
OMIM	108721
Orphanet	56305
ICD-11	1997882528
SNOMED CT	725142004
UMLS	C3668942
MedGen	777149
GARD	0010608
Is cancer (heuristic)	no

Also known as: AO3 · AOIII · atelosteogenesis type 3 · atelosteogenesis, type III

Data availability: 57 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › atelosteogenesis › atelosteogenesis type III

Related subtypes (2): atelosteogenesis type I, atelosteogenesis type II

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

57 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 18 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 not provided, 3 likely benign, 3 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
38961	NM_001457.4(FLNB):c.502G>A (p.Gly168Ser)	FLNB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6401	NM_001457.4(FLNB):c.604A>G (p.Met202Val)	FLNB	Pathogenic	no assertion criteria provided
6406	NM_001457.4(FLNB):c.5071G>A (p.Gly1691Ser)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
6402	NM_001457.4(FLNB):c.2251G>C (p.Gly751Arg)	FLNB	Likely pathogenic	criteria provided, single submitter
915265	NM_001457.4(FLNB):c.1739G>T (p.Gly580Val)	FLNB	Likely pathogenic	criteria provided, single submitter
932049	NM_001457.4(FLNB):c.644T>A (p.Ile215Asn)	FLNB	Likely pathogenic	criteria provided, single submitter
1306802	NM_001457.4(FLNB):c.3325G>A (p.Val1109Ile)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1356262	NM_001457.4(FLNB):c.1887C>G (p.Asp629Glu)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417463	NM_001457.4(FLNB):c.7036C>T (p.Arg2346Cys)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194935	NM_001457.4(FLNB):c.2773G>T (p.Gly925Cys)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252548	NM_001457.4(FLNB):c.808A>G (p.Met270Val)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2906029	NM_001457.4(FLNB):c.4313G>A (p.Arg1438His)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2963035	NM_001457.4(FLNB):c.4813C>T (p.Arg1605Cys)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346334	NM_001457.4(FLNB):c.3583G>A (p.Val1195Met)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346348	NM_001457.4(FLNB):c.5134G>A (p.Val1712Met)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346353	NM_001457.4(FLNB):c.5917G>A (p.Glu1973Lys)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346359	NM_001457.4(FLNB):c.6755A>T (p.Tyr2252Phe)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372367	NM_001457.4(FLNB):c.1588G>T (p.Gly530Trp)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372794	NM_001457.4(FLNB):c.572C>T (p.Pro191Leu)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3892281	NM_001457.4(FLNB):c.6073G>A (p.Val2025Met)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449027	NM_001457.4(FLNB):c.4730C>T (p.Ala1577Val)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899585	NM_001457.4(FLNB):c.4826C>T (p.Thr1609Ile)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930590	NM_001457.4(FLNB):c.6164G>A (p.Gly2055Asp)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931081	NM_001457.4(FLNB):c.7760G>T (p.Trp2587Leu)	FLNB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1328287	NM_001457.4(FLNB):c.2996G>A (p.Arg999Gln)	FLNB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372524	NM_001457.4(FLNB):c.6866G>A (p.Arg2289His)	FLNB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426840	NM_001457.4(FLNB):c.4589A>G (p.Tyr1530Cys)	FLNB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1480598	NM_001457.4(FLNB):c.3724+4G>C	FLNB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1488755	NM_001457.4(FLNB):c.3299T>G (p.Leu1100Arg)	FLNB	Uncertain significance	criteria provided, single submitter
1679680	NM_001457.4(FLNB):c.7351C>G (p.Leu2451Val)	FLNB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 5 · 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
FLNB	Definitive	Autosomal dominant	atelosteogenesis type I	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNB	Orphanet:1190	Atelosteogenesis type I
FLNB	Orphanet:1263	Boomerang dysplasia
FLNB	Orphanet:3275	Spondylocarpotarsal synostosis
FLNB	Orphanet:503	Larsen syndrome
FLNB	Orphanet:56305	Atelosteogenesis type III

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
FLNB	HGNC:3755	ENSG00000136068	O75369	Filamin-B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNB	Filamin-B	Connects cell membrane constituents to the actin cytoskeleton.

Protein-family classification

Druggable: 1 · 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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNB	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom

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
mucosa of transverse colon	1
tibial nerve	1
transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNB	290	ubiquitous	marker	mucosa of transverse colon, tibial nerve, transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNB	2,927

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNB	O75369	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
ISG15 antiviral mechanism	1	150.3×	0.007	FLNB

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
keratinocyte development	1	1532.0×	0.003	FLNB
epithelial cell morphogenesis	1	936.2×	0.003	FLNB
skeletal muscle tissue development	1	290.6×	0.007	FLNB
cellular response to type II interferon	1	208.1×	0.007	FLNB
actin cytoskeleton organization	1	79.1×	0.015	FLNB
signal transduction	1	16.1×	0.062	FLNB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLNB	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
FLNB	2	Binding:2

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	1	FLNB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FLNB	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.