Adams-Oliver syndrome 1

Summary

Adams-Oliver syndrome 1 (MONDO:0024506) is a disease caused by ARHGAP31 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ARHGAP31 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 68

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Adams-Oliver syndrome 1
Mondo ID	MONDO:0024506
OMIM	100300
UMLS	C4551482
MedGen	1635567
GARD	0025406
Is cancer (heuristic)	no

Also known as: Adams-Oliver syndrome 1 · Adams-Oliver syndrome caused by mutation in ARHGAP31 · AOS · AOS1 · ARHGAP31 Adams-Oliver syndrome

Data availability: 68 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 › Adams-Oliver syndrome › Adams-Oliver syndrome 1

Related subtypes (5): Adams-Oliver syndrome 2, Adams-Oliver syndrome 3, Adams-Oliver syndrome 4, Adams-Oliver syndrome 5, Adams-Oliver syndrome 6

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

68 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 22 benign, 9 benign/likely benign, 6 conflicting classifications of pathogenicity, 3 pathogenic, 2 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30857	NM_020754.4(ARHGAP31):c.2047C>T (p.Gln683Ter)	ARHGAP31	Pathogenic	no assertion criteria provided
30858	NM_020754.4(ARHGAP31):c.3260del (p.Lys1087fs)	ARHGAP31	Pathogenic	no assertion criteria provided
523589	NM_020754.4(ARHGAP31):c.2182C>T (p.Gln728Ter)	ARHGAP31	Pathogenic	criteria provided, single submitter
499360	NM_020812.4(DOCK6):c.3562C>T (p.Gln1188Ter)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1402061	NM_020754.4(ARHGAP31):c.688C>T (p.Arg230Trp)	ARHGAP31	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408682	NM_020754.4(ARHGAP31):c.3596C>T (p.Ala1199Val)	ARHGAP31	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2439151	NM_020754.4(ARHGAP31):c.482G>C (p.Ser161Thr)	ARHGAP31	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2575228	NM_020754.4(ARHGAP31):c.1150G>A (p.Gly384Ser)	ARHGAP31	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288159	NM_020754.4(ARHGAP31):c.2323G>A (p.Gly775Ser)	ARHGAP31	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638381	NM_020754.4(ARHGAP31):c.4139C>T (p.Thr1380Ile)	ARHGAP31	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028180	NM_020754.4(ARHGAP31):c.142C>T (p.His48Tyr)	ARHGAP31	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028181	NM_020754.4(ARHGAP31):c.3007G>A (p.Ala1003Thr)	ARHGAP31	Uncertain significance	criteria provided, single submitter
1028182	NM_020754.4(ARHGAP31):c.745A>G (p.Ser249Gly)	ARHGAP31	Uncertain significance	criteria provided, single submitter
1339129	NM_020754.4(ARHGAP31):c.3247G>A (p.Glu1083Lys)	ARHGAP31	Uncertain significance	criteria provided, single submitter
1683707	NM_020754.4(ARHGAP31):c.2471C>T (p.Ser824Phe)	ARHGAP31	Uncertain significance	criteria provided, single submitter
1806036	NM_020754.4(ARHGAP31):c.1487T>C (p.Leu496Pro)	ARHGAP31	Uncertain significance	criteria provided, single submitter
1806229	NM_020754.4(ARHGAP31):c.3199A>G (p.Ser1067Gly)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2083861	NM_020754.4(ARHGAP31):c.3698A>T (p.Gln1233Leu)	ARHGAP31	Uncertain significance	criteria provided, multiple submitters, no conflicts
2186141	NM_020754.4(ARHGAP31):c.1345A>G (p.Lys449Glu)	ARHGAP31	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439150	NM_020754.4(ARHGAP31):c.4289G>A (p.Arg1430Gln)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2439152	NM_020754.4(ARHGAP31):c.1276C>G (p.Arg426Gly)	ARHGAP31	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439153	NM_020754.4(ARHGAP31):c.1063G>T (p.Val355Leu)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2439154	NM_020754.4(ARHGAP31):c.3223G>A (p.Val1075Met)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2439155	NM_020754.4(ARHGAP31):c.3545G>A (p.Ser1182Asn)	ARHGAP31	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585092	NM_020754.4(ARHGAP31):c.1807G>A (p.Glu603Lys)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2672252	NM_020754.4(ARHGAP31):c.1462G>C (p.Glu488Gln)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2672262	NM_020754.4(ARHGAP31):c.3635T>C (p.Ile1212Thr)	ARHGAP31	Uncertain significance	criteria provided, single submitter
2688592	NM_020754.4(ARHGAP31):c.1220C>A (p.Ala407Asp)	ARHGAP31	Uncertain significance	criteria provided, single submitter
3065855	NM_020754.4(ARHGAP31):c.349-1G>A	ARHGAP31	Uncertain significance	criteria provided, single submitter
3234935	NM_020754.4(ARHGAP31):c.4271del (p.Cys1424fs)	ARHGAP31	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
ARHGAP31	Strong	Autosomal dominant	Adams-Oliver syndrome 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARHGAP31	Orphanet:974	Adams-Oliver syndrome
DOCK6	Orphanet:974	Adams-Oliver syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARHGAP31	HGNC:29216	ENSG00000031081	Q2M1Z3	Rho GTPase-activating protein 31	gencc,clinvar
DOCK6	HGNC:19189	ENSG00000130158	Q96HP0	Dedicator of cytokinesis protein 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARHGAP31	Rho GTPase-activating protein 31	Functions as a GTPase-activating protein (GAP) for RAC1 and CDC42.
DOCK6	Dedicator of cytokinesis protein 6	Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGAP31	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, PX-Rho_GAP
DOCK6	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
apex of heart	1
colonic epithelium	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGAP31	241	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, myocardium
DOCK6	254	ubiquitous	marker	colonic epithelium, right lung, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DOCK6	1,018
ARHGAP31	809

Intra-cohort edges

A	B	Sources
ARHGAP31	DOCK6	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DOCK6	Q96HP0	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARHGAP31	Q2M1Z3	43.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CDC42 GTPase cycle	2	72.3×	7e-04	ARHGAP31, DOCK6
RAC1 GTPase cycle	2	61.1×	7e-04	ARHGAP31, DOCK6
RHOU GTPase cycle	1	139.3×	0.012	ARHGAP31
RHOA GTPase cycle	1	37.3×	0.030	ARHGAP31
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.030	DOCK6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
small GTPase-mediated signal transduction	2	183.2×	9e-05	ARHGAP31, DOCK6
regulation of Rho protein signal transduction	1	255.3×	0.006	DOCK6
regulation of small GTPase mediated signal transduction	1	72.0×	0.014	ARHGAP31

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
ARHGAP31	0	0
DOCK6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	ARHGAP31, DOCK6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARHGAP31	0	—
DOCK6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.