polydactyly, postaxial, type A8

Summary

polydactyly, postaxial, type A8 (MONDO:0029130) is a disease caused by GLI1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GLI1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polydactyly, postaxial, type A8
Mondo ID	MONDO:0029130
OMIM	618123
UMLS	C4748277
MedGen	1648405
GARD	0016293
Is cancer (heuristic)	no

Also known as: PAPA8 · polydactyly, postaxial, type A8

Data availability: 12 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › polydactyly › non-syndromic polydactyly › postaxial polydactyly › postaxial polydactyly type A › polydactyly, postaxial, type A8

Related subtypes (9): polydactyly, postaxial, type A1, polydactyly, postaxial, type A5, polydactyly, postaxial, type A2, polydactyly, postaxial, type A3, polydactyly, postaxial, type A4, polydactyly, postaxial, type A6, postaxial polydactyly type A, unilateral, postaxial polydactyly type A, bilateral, polydactyly, postaxial, type a7

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

12 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 uncertain significance, 3 benign, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3390852	NM_005269.3(GLI1):c.1013G>T (p.Cys338Phe)	GLI1	Pathogenic	criteria provided, single submitter
561213	NM_005269.3(GLI1):c.2340G>A (p.Trp780Ter)	GLI1	Pathogenic	criteria provided, single submitter
561214	NM_005269.3(GLI1):c.1930C>T (p.Gln644Ter)	GLI1	Pathogenic	no assertion criteria provided
561215	NM_005269.3(GLI1):c.337C>T (p.Arg113Ter)	GLI1	Pathogenic	criteria provided, single submitter
982420	NM_005269.3(GLI1):c.985A>T (p.Lys329Ter)	GLI1	Likely pathogenic	criteria provided, single submitter
2429115	NM_005269.3(GLI1):c.816G>T (p.Trp272Cys)	GLI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032306	NM_005269.3(GLI1):c.3065del (p.Gly1022fs)	GLI1	Uncertain significance	criteria provided, single submitter
1709702	NM_005269.3(GLI1):c.877C>T (p.Arg293Cys)	GLI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
626906	NM_005269.3(GLI1):c.1517T>A (p.Leu506Gln)	GLI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1240928	NM_005269.3(GLI1):c.2798G>A (p.Gly933Asp)	GLI1	Benign	criteria provided, multiple submitters, no conflicts
1277191	NM_005269.3(GLI1):c.576G>A (p.Glu192=)	GLI1	Benign	criteria provided, multiple submitters, no conflicts
1285295	NM_005269.3(GLI1):c.3298G>C (p.Glu1100Gln)	GLI1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
GLI1	Strong	Autosomal dominant	postaxial polydactyly	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI1	Orphanet:289	Ellis Van Creveld syndrome
GLI1	Orphanet:93334	Postaxial polydactyly type A
GLI1	Orphanet:93335	Postaxial polydactyly type B
GLI1	Orphanet:93339	Polydactyly of a biphalangeal thumb and/or hallux

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
GLI1	HGNC:4317	ENSG00000111087	P08151	Zinc finger protein GLI1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI1	Zinc finger protein GLI1	Acts as a transcriptional activator.

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)
GLI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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
olfactory bulb	1
tibial nerve	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI1	173	broad	yes	tibial nerve, olfactory bulb, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI1	4,101

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLI1	P08151	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	1631.4×	0.002	GLI1
Degradation of GLI1 by the proteasome	1	223.9×	0.006	GLI1
Hedgehog ‘off’ state	1	178.4×	0.006	GLI1
Hedgehog ‘on’ state	1	158.6×	0.006	GLI1

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
notochord regression	1	16852.0×	0.002	GLI1
regulation of hepatocyte proliferation	1	8426.0×	0.002	GLI1
ventral midline development	1	5617.3×	0.002	GLI1
regulation of cerebellar granule cell precursor proliferation	1	4213.0×	0.002	GLI1
cerebellar cortex morphogenesis	1	2808.7×	0.002	GLI1
epidermal cell differentiation	1	1685.2×	0.003	GLI1
prostate gland development	1	1404.3×	0.003	GLI1
regulation of osteoblast differentiation	1	1296.3×	0.003	GLI1
positive regulation of cell cycle G1/S phase transition	1	1123.5×	0.003	GLI1
digestive tract morphogenesis	1	991.3×	0.003	GLI1
proximal/distal pattern formation	1	648.1×	0.003	GLI1
pituitary gland development	1	648.1×	0.003	GLI1
regulation of smoothened signaling pathway	1	624.1×	0.003	GLI1
positive regulation of cardiac muscle cell proliferation	1	624.1×	0.003	GLI1
positive regulation of DNA replication	1	581.1×	0.003	GLI1
liver regeneration	1	510.7×	0.004	GLI1
dorsal/ventral pattern formation	1	421.3×	0.004	GLI1
positive regulation of smoothened signaling pathway	1	421.3×	0.004	GLI1
response to wounding	1	221.7×	0.007	GLI1
lung development	1	198.3×	0.008	GLI1
smoothened signaling pathway	1	181.2×	0.008	GLI1
spermatid development	1	145.3×	0.009	GLI1
osteoblast differentiation	1	121.2×	0.011	GLI1
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.011	GLI1
positive regulation of cell migration	1	61.7×	0.019	GLI1
positive regulation of cell population proliferation	1	33.6×	0.034	GLI1
regulation of DNA-templated transcription	1	31.6×	0.035	GLI1
positive regulation of DNA-templated transcription	1	27.9×	0.038	GLI1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	GLI1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	GLI1

Therapeutics

Drug target analysis

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

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
GLI1	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BETULINIC ACID	1	GLI1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GLI1	44	Binding:44

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
BETULINIC ACID	1	GLI1

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	1	GLI1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.