polydactyly, postaxial, type A1

Summary

polydactyly, postaxial, type A1 (MONDO:0008266) is a disease caused by GLI3 (GenCC Strong), with 8 cohort genes.

At a glance

• Causal gene: GLI3 (GenCC Strong)
• Cohort genes: 8
• ClinVar variants: 289

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polydactyly, postaxial, type A1
Mondo ID	MONDO:0008266
OMIM	174200
UMLS	C4282400
MedGen	924305
GARD	0004414
Is cancer (heuristic)	no

Also known as: PAPA1 · polydactyly, postaxial, type A1 · polydactyly, postaxial, types A1 and B

Data availability: 289 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 A1

Related subtypes (9): 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 A8, 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

289 retrieved; paginated sample, class counts are floors:

148 uncertain significance, 58 conflicting classifications of pathogenicity, 27 benign/likely benign, 22 likely benign, 18 pathogenic, 6 likely pathogenic, 5 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
638151	NM_001692.4(ATP6V1B1):c.175-1G>C	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1147	NM_152618.3(BBS12):c.1063C>T (p.Arg355Ter)	BBS12	Pathogenic	criteria provided, multiple submitters, no conflicts
523401	NM_001378615.1(CC2D2A):c.1149+1G>A	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56312	NM_001378615.1(CC2D2A):c.4179+1del	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1120234	NM_000168.6(GLI3):c.1880_1881del (p.His627fs)	GLI3	Pathogenic	criteria provided, multiple submitters, no conflicts
1120236	NM_000168.6(GLI3):c.366C>A (p.Tyr122Ter)	GLI3	Pathogenic	criteria provided, single submitter
1120237	NM_000168.6(GLI3):c.650C>G (p.Ser217Ter)	GLI3	Pathogenic	criteria provided, single submitter
1120238	NM_000168.6(GLI3):c.1033_1048del (p.Ala345fs)	GLI3	Pathogenic	criteria provided, single submitter
1120239	NM_000168.6(GLI3):c.2103+2T>A	GLI3	Pathogenic	criteria provided, single submitter
1120240	NM_000168.6(GLI3):c.2594C>G (p.Ser865Ter)	GLI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1120244	NM_000168.6(GLI3):c.2059del (p.Glu687fs)	GLI3	Pathogenic	criteria provided, single submitter
13816	GLI3, CODON 764, FS	GLI3	Pathogenic	no assertion criteria provided
13828	NM_000168.6(GLI3):c.2374C>T (p.Arg792Ter)	GLI3	Pathogenic	criteria provided, multiple submitters, no conflicts
3382660	NM_000168.6(GLI3):c.2128C>T (p.Gln710Ter)	GLI3	Pathogenic	criteria provided, single submitter
3391005	NM_000168.6(GLI3):c.4564del (p.Ala1522fs)	GLI3	Pathogenic	criteria provided, single submitter
3392509	NM_000168.6(GLI3):c.999_1002dup (p.Gly335fs)	GLI3	Pathogenic	criteria provided, single submitter
374325	NM_000168.6(GLI3):c.2252del (p.Asp751fs)	GLI3	Pathogenic	no assertion criteria provided
393462	NM_000168.6(GLI3):c.3635del (p.Gly1212fs)	GLI3	Pathogenic	no assertion criteria provided
4531290	NM_000168.6(GLI3):c.1681G>T (p.Glu561Ter)	GLI3	Pathogenic	criteria provided, single submitter
528802	NM_000168.6(GLI3):c.1028+1G>A	GLI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638150	NM_152558.5(IQCE):c.1350_1353del	IQCE	Pathogenic	criteria provided, multiple submitters, no conflicts
599403	NM_001145678.3(KIAA0825):c.591dup (p.Gln198fs)	KIAA0825	Pathogenic/Likely pathogenic	no assertion criteria provided
30261	NM_003322.6(TULP1):c.1198C>T (p.Arg400Trp)	TULP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1120242	NM_000168.6(GLI3):c.1880A>C (p.His627Pro)	GLI3	Likely pathogenic	criteria provided, single submitter
1679363	NM_000168.6(GLI3):c.4346del (p.Gly1449fs)	GLI3	Likely pathogenic	criteria provided, single submitter
1687456	NM_000168.6(GLI3):c.1693del (p.Thr565fs)	GLI3	Likely pathogenic	criteria provided, single submitter
3062247	NM_000168.6(GLI3):c.1325_1328dup (p.Ser445fs)	GLI3	Likely pathogenic	criteria provided, single submitter
3062311	NM_000168.6(GLI3):c.2876_2880dup (p.Gly961fs)	GLI3	Likely pathogenic	criteria provided, single submitter
3067137	NM_000168.6(GLI3):c.2151del (p.Gln717fs)	GLI3	Likely pathogenic	criteria provided, single submitter
1040568	NM_000168.6(GLI3):c.3611C>G (p.Pro1204Arg)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 22 · 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
GLI3	Strong	Autosomal dominant	polydactyly, postaxial, type A1	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly
TULP1	Orphanet:65	Leber congenital amaurosis
TULP1	Orphanet:791	Retinitis pigmentosa
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa
BBS12	Orphanet:110	Bardet-Biedl syndrome
KIAA0825	Orphanet:93334	Postaxial polydactyly type A
IQCE	Orphanet:93334	Postaxial polydactyly type A
CC2D2A	Orphanet:1454	Joubert syndrome with hepatic defect
CC2D2A	Orphanet:2318	Joubert syndrome with oculorenal defect
CC2D2A	Orphanet:564	Meckel syndrome
CC2D2A	Orphanet:791	Retinitis pigmentosa
ATP6V1B1	Orphanet:402041	Autosomal recessive distal renal tubular acidosis

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	gencc,clinvar
TULP1	HGNC:12423	ENSG00000112041	O00294	Tubby-related protein 1	clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar
BBS12	HGNC:26648	ENSG00000181004	Q6ZW61	Chaperonin-containing T-complex member BBS12	clinvar
KIAA0825	HGNC:28532	ENSG00000185261	Q8IV33	Uncharacterized protein KIAA0825	clinvar
IQCE	HGNC:29171	ENSG00000106012	Q6IPM2	IQ domain-containing protein E	clinvar
CC2D2A	HGNC:29253	ENSG00000048342	Q9P2K1	Coiled-coil and C2 domain-containing protein 2A	clinvar
ATP6V1B1	HGNC:853	ENSG00000116039	P15313	V-type proton ATPase subunit B, kidney isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.
TULP1	Tubby-related protein 1	Required for normal development of photoreceptor synapses.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.
BBS12	Chaperonin-containing T-complex member BBS12	Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis.
IQCE	IQ domain-containing protein E	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
CC2D2A	Coiled-coil and C2 domain-containing protein 2A	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
ATP6V1B1	V-type proton ATPase subunit B, kidney isoform	Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 6 · Druggable fraction: 0.12

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
Protease	1	4.6×	0.352
Other/Unknown	6	1.3×	0.352
Transcription factor	1	1.0×	0.644

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
TULP1	Other/Unknown	no		Tubby_C, Tubby_C_CS, Tubby-like_C
OFD1	Other/Unknown	no		LisH, OFD1
BBS12	Other/Unknown	no		Cpn60/GroEL/TCP-1, GroEL-like_apical_dom_sf, TCP-1-like_intermed_sf
KIAA0825	Other/Unknown	no		DUF4495
IQCE	Other/Unknown	no		IQ_motif_EF-hand-BS, CellDiv_DevSignal_Domain
CC2D2A	Protease	yes		C2_dom, CC2D2AN-C2, C2_domain_sf
ATP6V1B1	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_bsu

Expression context

Cohort genes with no expression data: 0.

7 cohort genes 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	3
tendon of biceps brachii	2
primordial germ cell in gonad	2
sperm	2
male germ line stem cell (sensu Vertebrata) in testis	2
right uterine tube	2
olfactory bulb	1
ventricular zone	1
retina	1
cervix squamous epithelium	1
adrenal tissue	1
calcaneal tendon	1
left testis	1
right testis	1
sural nerve	1
bronchus	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii
TULP1	134	tissue_specific	marker	primordial germ cell in gonad, tendon of biceps brachii, retina
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium
BBS12	204	ubiquitous	yes	primordial germ cell in gonad, sperm, bronchial epithelial cell
KIAA0825	167	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, calcaneal tendon
IQCE	231	ubiquitous	marker	left testis, right testis, sural nerve
CC2D2A	247	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus
ATP6V1B1	152	broad	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OFD1	2,878
GLI3	2,825
ATP6V1B1	2,172
IQCE	1,124
CC2D2A	899
TULP1	760
BBS12	653
KIAA0825	469

Intra-cohort edges

A	B	Sources
CC2D2A	OFD1	biogrid_interaction, intact, string_interaction
IQCE	KIAA0825	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TULP1	O00294	2
GLI3	P10071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V1B1	P15313	87.21
KIAA0825	Q8IV33	74.33
BBS12	Q6ZW61	73.92
CC2D2A	Q9P2K1	69.46
IQCE	Q6IPM2	69.36
OFD1	O75665	68.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hedgehog ‘off’ state	2	59.5×	0.007	GLI3, OFD1
Hedgehog ‘on’ state	2	52.9×	0.007	GLI3, IQCE
Anchoring of the basal body to the plasma membrane	2	37.7×	0.007	OFD1, CC2D2A
Cilium Assembly	2	36.2×	0.007	BBS12, CC2D2A
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	271.9×	0.015	GLI3
Organelle biogenesis and maintenance	2	22.0×	0.015	BBS12, CC2D2A
Activation of SMO	1	105.7×	0.032	IQCE
BBSome-mediated cargo-targeting to cilium	1	82.8×	0.035	BBS12
RUNX2 regulates osteoblast differentiation	1	76.1×	0.035	GLI3
Insulin receptor recycling	1	63.4×	0.035	ATP6V1B1
Transferrin endocytosis and recycling	1	61.4×	0.035	ATP6V1B1
ROS and RNS production in phagocytes	1	56.0×	0.035	ATP6V1B1
Cargo trafficking to the periciliary membrane	1	41.4×	0.044	BBS12
GLI3 is processed to GLI3R by the proteasome	1	37.3×	0.045	GLI3
Amino acids regulate mTORC1	1	33.4×	0.047	ATP6V1B1
Signaling by Hedgehog	1	30.7×	0.048	IQCE
Loss of Nlp from mitotic centrosomes	1	26.4×	0.049	OFD1
Loss of proteins required for interphase microtubule organization from the centrosome	1	26.4×	0.049	OFD1
AURKA Activation by TPX2	1	25.4×	0.049	OFD1
Recruitment of mitotic centrosome proteins and complexes	1	22.7×	0.052	OFD1
Regulation of PLK1 Activity at G2/M Transition	1	21.1×	0.053	OFD1
Recruitment of NuMA to mitotic centrosomes	1	19.4×	0.055	OFD1
Ion channel transport	1	16.0×	0.064	ATP6V1B1
Signal Transduction	1	1.7×	0.463	IQCE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
limb morphogenesis	2	300.9×	0.002	GLI3, IQCE
axoneme assembly	2	155.3×	0.004	OFD1, CC2D2A
lateral ganglionic eminence cell proliferation	1	2407.4×	0.006	GLI3
lambdoid suture morphogenesis	1	2407.4×	0.006	GLI3
sagittal suture morphogenesis	1	2407.4×	0.006	GLI3
mammary gland specification	1	2407.4×	0.006	GLI3
anterior semicircular canal development	1	2407.4×	0.006	GLI3
lateral semicircular canal development	1	2407.4×	0.006	GLI3
photoreceptor cell maintenance	2	102.4×	0.006	TULP1, BBS12
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	1203.7×	0.007	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	1203.7×	0.007	GLI3
larynx morphogenesis	1	1203.7×	0.007	GLI3
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	1203.7×	0.007	OFD1
smoothened signaling pathway	2	51.8×	0.007	GLI3, CC2D2A
nose morphogenesis	1	802.5×	0.008	GLI3
negative regulation of alpha-beta T cell differentiation	1	802.5×	0.008	GLI3
frontal suture morphogenesis	1	802.5×	0.008	GLI3
cell differentiation involved in kidney development	1	802.5×	0.008	GLI3
renal tubular secretion	1	802.5×	0.008	ATP6V1B1
renal sodium ion transport	1	601.9×	0.009	ATP6V1B1
hindgut morphogenesis	1	601.9×	0.009	GLI3
renal sodium excretion	1	601.9×	0.009	ATP6V1B1
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	601.9×	0.009	GLI3
optic nerve morphogenesis	1	481.5×	0.010	GLI3
regulation of bone development	1	481.5×	0.010	GLI3
forebrain radial glial cell differentiation	1	401.2×	0.011	GLI3
vacuolar proton-transporting V-type ATPase complex assembly	1	401.2×	0.011	ATP6V1B1
pH reduction	1	343.9×	0.012	ATP6V1B1
protein localization to photoreceptor outer segment	1	343.9×	0.012	TULP1
protein localization to ciliary transition zone	1	343.9×	0.012	CC2D2A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 1 of 8 evidence-associated genes (12%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLI3	0	0
TULP1	0	0
OFD1	0	0
BBS12	0	0
KIAA0825	0	0
IQCE	0	0
CC2D2A	0	0
ATP6V1B1	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
ATP6V1B1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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	1	CC2D2A
E	Difficult family or no structure, no drug	7	GLI3, TULP1, OFD1, BBS12, KIAA0825, IQCE, ATP6V1B1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GLI3	0	—
TULP1	0	—
OFD1	0	—
BBS12	0	—
KIAA0825	0	—
IQCE	0	—
CC2D2A	0	—
ATP6V1B1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.