Martsolf syndrome

Summary

Martsolf syndrome (MONDO:0023910) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 550

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Martsolf syndrome
Mondo ID	MONDO:0023910
OMIM	212720
UMLS	C0796037
MedGen	208658
GARD	0025377
Is cancer (heuristic)	no

Data availability: 550 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › RAB18 deficiency › Martsolf syndrome

Related subtypes (1): Warburg micro syndrome

Subtypes (2): Martsolf syndrome 2, Martsolf syndrome 1

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

550 retrieved; paginated sample, class counts are floors:

235 uncertain significance, 230 likely benign, 33 conflicting classifications of pathogenicity, 20 benign, 14 benign/likely benign, 10 pathogenic, 7 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425804	NC_000001.10:g.(?218520044)(220986760_?)del	MIR194-1	Pathogenic	criteria provided, single submitter
545408	NM_012233.3(RAB3GAP1):c.9del (p.Asp4fs)	RAB3GAP1	Pathogenic	no assertion criteria provided
100787	NM_012414.4(RAB3GAP2):c.1276C>T (p.Arg426Cys)	RAB3GAP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030256	NM_012414.4(RAB3GAP2):c.2366_2370delinsGACTGTGG (p.Gln789_Ser790delinsArgLeuTrp)	RAB3GAP2	Pathogenic	criteria provided, single submitter
1435827	NM_012414.4(RAB3GAP2):c.1998+1G>A	RAB3GAP2	Pathogenic	criteria provided, single submitter
1820	NM_012414.4(RAB3GAP2):c.3154G>T (p.Gly1052Cys)	RAB3GAP2	Pathogenic	no assertion criteria provided
2193003	NM_012414.4(RAB3GAP2):c.694C>T (p.Arg232Ter)	RAB3GAP2	Pathogenic	criteria provided, single submitter
2415504	NM_012414.4(RAB3GAP2):c.1348dup (p.Ser450fs)	RAB3GAP2	Pathogenic	criteria provided, single submitter
2425802	NC_000001.10:g.(?220330592)(220335630_?)del	RAB3GAP2	Pathogenic	criteria provided, single submitter
2921941	NM_012414.4(RAB3GAP2):c.340del (p.Met114fs)	RAB3GAP2	Pathogenic	criteria provided, single submitter
2952637	NM_012414.4(RAB3GAP2):c.3613del (p.Met1205fs)	RAB3GAP2	Pathogenic	criteria provided, single submitter
2945467	NM_012414.4(RAB3GAP2):c.1715-1G>A	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
3247714	NC_000001.10:g.(?220345211)(220375736_?)dup	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
4786492	NM_012414.4(RAB3GAP2):c.960+1G>A	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
4792184	NM_012414.4(RAB3GAP2):c.3262-2A>G	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
870510	NM_012414.4(RAB3GAP2):c.387-2A>G	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
870511	NM_012414.4(RAB3GAP2):c.1283C>A (p.Ala428Glu)	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
981015	NM_012414.4(RAB3GAP2):c.3385G>A (p.Asp1129Asn)	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
1151064	NM_012414.4(RAB3GAP2):c.511-7C>T	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1188577	NM_012414.4(RAB3GAP2):c.2176A>G (p.Ile726Val)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1204990	NM_012414.4(RAB3GAP2):c.33C>G (p.Phe11Leu)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1254758	NM_012414.4(RAB3GAP2):c.2282C>T (p.Ser761Leu)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130073	NM_012414.4(RAB3GAP2):c.774A>G (p.Leu258=)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1933933	NM_012414.4(RAB3GAP2):c.2578-6dup	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2037404	NM_012414.4(RAB3GAP2):c.3940C>T (p.His1314Tyr)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208607	NM_012414.4(RAB3GAP2):c.713-2A>G	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211984	NM_012414.4(RAB3GAP2):c.2008C>G (p.Leu670Val)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211987	NM_012414.4(RAB3GAP2):c.3525C>T (p.Thr1175=)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211989	NM_012414.4(RAB3GAP2):c.4060A>G (p.Ile1354Val)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211991	NM_012414.4(RAB3GAP2):c.504C>T (p.Tyr168=)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB3GAP1	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP1	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP2	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:401830	Autosomal recessive spastic paraplegia type 69
IARS2	Orphanet:436174	Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
IARS2	Orphanet:506	Leigh syndrome

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAB3GAP1	HGNC:17063	ENSG00000115839	Q15042	Rab3 GTPase-activating protein catalytic subunit	clinvar
RAB3GAP2	HGNC:17168	ENSG00000118873	Q9H2M9	Rab3 GTPase-activating protein non-catalytic subunit	clinvar
IARS2	HGNC:29685	ENSG00000067704	Q9NSE4	Isoleucine–tRNA ligase, mitochondrial	clinvar
MIR194-1	HGNC:31564	ENSG00000207624		microRNA 194-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB3GAP1	Rab3 GTPase-activating protein catalytic subunit	Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
RAB3GAP2	Rab3 GTPase-activating protein non-catalytic subunit	Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
IARS2	Isoleucine–tRNA ligase, mitochondrial	Aminoacyl-tRNA synthetase that catalyzes the specific attachment of isoleucine to its cognate tRNA (tRNA(Ile)).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAB3GAP1	Other/Unknown	no		Rab3GAP1_conserved, Rab3GAP1_C, Rab3GAP1
RAB3GAP2	Other/Unknown	no		Rab3GAP2, RAB3GAP2_C, RAB3GAP_N
IARS2	Transcription factor	no	6.1.1.5	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Ile-tRNA-ligase
MIR194-1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
hair follicle	1
secondary oocyte	1
choroid plexus epithelium	1
dorsal root ganglion	1
lateral nuclear group of thalamus	1
diaphragm	1
parietal pleura	1
skeletal muscle tissue of biceps brachii	1
adrenal tissue	1
amygdala	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB3GAP1	300	ubiquitous	marker	hair follicle, Brodmann (1909) area 23, secondary oocyte
RAB3GAP2	295	ubiquitous	marker	choroid plexus epithelium, lateral nuclear group of thalamus, dorsal root ganglion
IARS2	293	ubiquitous	marker	diaphragm, parietal pleura, skeletal muscle tissue of biceps brachii
MIR194-1	91		yes	amygdala, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IARS2	3,442
RAB3GAP1	2,039
RAB3GAP2	1,794
MIR194-1	0

Intra-cohort edges

A	B	Sources
RAB3GAP1	RAB3GAP2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAB3GAP1	Q15042	1
RAB3GAP2	Q9H2M9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IARS2	Q9NSE4	89.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPI-independent Golgi-to-ER retrograde traffic	2	138.4×	5e-04	RAB3GAP1, RAB3GAP2
RAB GEFs exchange GTP for GDP on RABs	2	82.8×	7e-04	RAB3GAP1, RAB3GAP2
Mitochondrial tRNA aminoacylation	1	173.0×	0.013	IARS2
tRNA Aminoacylation	1	95.2×	0.018	IARS2
Mitochondrial protein degradation	1	38.1×	0.036	IARS2
Translation	1	20.7×	0.055	IARS2
Metabolism of proteins	1	4.1×	0.223	IARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
establishment of protein localization to endoplasmic reticulum membrane	2	3744.9×	9e-07	RAB3GAP1, RAB3GAP2
positive regulation of protein lipidation	2	2808.7×	9e-07	RAB3GAP1, RAB3GAP2
positive regulation of endoplasmic reticulum tubular network organization	2	2808.7×	9e-07	RAB3GAP1, RAB3GAP2
positive regulation of autophagosome assembly	2	535.0×	2e-05	RAB3GAP1, RAB3GAP2
isoleucyl-tRNA aminoacylation	1	2808.7×	0.001	IARS2
positive regulation of glutamate neurotransmitter secretion in response to membrane depolarization	1	2808.7×	0.001	RAB3GAP1
regulation of calcium ion-dependent exocytosis of neurotransmitter	1	2808.7×	0.001	RAB3GAP1
synaptic signaling	1	510.7×	0.005	RAB3GAP2
regulation of short-term neuronal synaptic plasticity	1	374.5×	0.006	RAB3GAP1
hypothalamus development	1	351.1×	0.006	RAB3GAP1
Rab protein signal transduction	1	330.4×	0.006	RAB3GAP1
lipid droplet organization	1	312.1×	0.006	RAB3GAP1
tRNA aminoacylation for protein translation	1	280.9×	0.006	IARS2
regulation of GTPase activity	1	170.2×	0.008	RAB3GAP2
face morphogenesis	1	165.2×	0.008	RAB3GAP1
excitatory postsynaptic potential	1	147.8×	0.009	RAB3GAP1
camera-type eye development	1	119.5×	0.010	RAB3GAP1
macroautophagy	1	80.2×	0.014	RAB3GAP2
mitochondrial translation	1	57.9×	0.019	IARS2
brain development	1	26.5×	0.039	RAB3GAP1
intracellular protein transport	1	21.6×	0.046	RAB3GAP2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IARS2	1	2
RAB3GAP1	0	0
RAB3GAP2	0	0
MIR194-1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PIMASERTIB	2	IARS2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
IARS2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IARS2	6.1.1.5	isoleucine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
PIMASERTIB	2	IARS2

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	IARS2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	RAB3GAP1, RAB3GAP2, MIR194-1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RAB3GAP1	0	—
RAB3GAP2	0	—
MIR194-1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.