RIN2 syndrome

Summary

RIN2 syndrome (MONDO:0013115) is a disease caused by RIN2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RIN2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 27
• Phenotypes (HPO): 28
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000159	Abnormal lip morphology	Very frequent (80-99%)
HP:0000212	Gingival overgrowth	Very frequent (80-99%)
HP:0000218	High palate	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001007	Hirsutism	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0001763	Pes planus	Very frequent (80-99%)
HP:0002209	Sparse scalp hair	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0011232	Infra-orbital fold	Very frequent (80-99%)
HP:0012724	Upper eyelid edema	Very frequent (80-99%)
HP:0040079	Irregular dentition	Very frequent (80-99%)
HP:0000766	Abnormal sternum morphology	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001620	Abnormally high-pitched voice	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000815	Hypergonadotropic hypogonadism	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0004942	Aortic aneurysm	Occasional (5-29%)
HP:0008209	Premature ovarian insufficiency	Occasional (5-29%)
HP:0011003	High myopia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	RIN2 syndrome
Mondo ID	MONDO:0013115
MeSH	C567770
OMIM	613075
Orphanet	217335
SNOMED CT	723367005
UMLS	C2751321
MedGen	416526
GARD	0017120
Is cancer (heuristic)	no

Also known as: macrocephaly-alopecia-cutis laxa-scoliosis syndrome · MACS syndrome · RIN2 deficiency · RIN2 syndrome · tall forehead-sparse hair-skin hyperextensibility-scoliosis syndrome

Data availability: 27 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited cutis laxa › RIN2 syndrome

Related subtypes (13): craniofaciofrontodigital syndrome, arterial tortuosity syndrome, ALDH18A1-related de Barsy syndrome, autosomal recessive cutis laxa type 2, classic type, geroderma osteodysplastica, occipital horn syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, PYCR1-related de Barsy syndrome, autosomal dominant cutis laxa, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, cutis laxa, autosomal recessive, type 2E, arterial tortuosity-bone fragility syndrome

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

27 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 conflicting classifications of pathogenicity, 3 benign, 3 pathogenic, 3 benign/likely benign, 2 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1296	NM_018993.4(RIN2):c.1731del (p.Ile578fs)	RIN2	Pathogenic	criteria provided, single submitter
137627	NM_018993.4(RIN2):c.1731dup (p.Ile578fs)	RIN2	Pathogenic	criteria provided, single submitter
36923	NM_018993.4(RIN2):c.1914_1915del (p.Glu638fs)	RIN2	Pathogenic	no assertion criteria provided
590794	NM_018993.4(RIN2):c.2104dup (p.Leu702fs)	RIN2	Likely pathogenic	criteria provided, single submitter
804430	NM_018993.4(RIN2):c.277_278dup (p.His94fs)	RIN2	Likely pathogenic	criteria provided, single submitter
1187886	NM_018993.4(RIN2):c.41G>A (p.Arg14Gln)	RIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1203399	NM_018993.4(RIN2):c.404G>A (p.Arg135His)	RIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1359762	NM_018993.4(RIN2):c.28G>A (p.Gly10Ser)	RIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2961265	NM_018993.4(RIN2):c.695C>T (p.Ser232Phe)	RIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374444	NM_018993.4(RIN2):c.1642G>A (p.Val548Met)	RIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303295	NM_018993.4(RIN2):c.922C>G (p.Pro308Ala)	RIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348826	NM_018993.4(RIN2):c.2518G>A (p.Val840Ile)	RIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1447737	NM_018993.4(RIN2):c.1019A>G (p.His340Arg)	RIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
212056	NM_018993.4(RIN2):c.923C>A (p.Pro308Gln)	RIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435435	NM_018993.4(RIN2):c.1555G>C (p.Ala519Pro)	RIN2	Uncertain significance	criteria provided, single submitter
2435436	NM_018993.4(RIN2):c.2492del (p.Pro831fs)	RIN2	Uncertain significance	criteria provided, single submitter
3587101	NM_018993.4(RIN2):c.1427C>T (p.Pro476Leu)	RIN2	Uncertain significance	criteria provided, single submitter
421543	NM_018993.4(RIN2):c.797A>T (p.Asn266Ile)	RIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
451390	NM_018993.4(RIN2):c.2398A>T (p.Ser800Cys)	RIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1282512	NM_018993.4(RIN2):c.2201-47G>A	RIN2	Benign	criteria provided, multiple submitters, no conflicts
1327956	NM_018993.4(RIN2):c.899G>A (p.Gly300Asp)	RIN2	Likely benign	criteria provided, single submitter
1550777	NM_018993.4(RIN2):c.159-17G>A	RIN2	Likely benign	criteria provided, multiple submitters, no conflicts
212055	NM_018993.4(RIN2):c.84C>T (p.Ile28=)	RIN2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
257654	NM_018993.4(RIN2):c.1818C>T (p.His606=)	RIN2	Benign	criteria provided, multiple submitters, no conflicts
390346	NM_018993.4(RIN2):c.85G>A (p.Gly29Arg)	RIN2	Benign	criteria provided, multiple submitters, no conflicts
436538	NM_018993.4(RIN2):c.2436C>T (p.Tyr812=)	RIN2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
509960	NM_018993.4(RIN2):c.1851C>T (p.Ala617=)	RIN2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
RIN2	Definitive	Autosomal recessive	RIN2 syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIN2	Orphanet:217335	RIN2 syndrome

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
RIN2	HGNC:18750	ENSG00000132669	Q8WYP3	Ras and Rab interactor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIN2	Ras and Rab interactor 2	Ras effector protein.

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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RIN2	Scaffold/PPI	no		RA_dom, SH2, VPS9

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
choroid plexus epithelium	1
hair follicle	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIN2	296	ubiquitous	marker	choroid plexus epithelium, tendon of biceps brachii, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIN2	707

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RIN2	Q8WYP3	64.30

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
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	RIN2

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
positive regulation of endothelial cell-matrix adhesion	1	2106.5×	0.002	RIN2
positive regulation of vasculogenesis	1	1296.3×	0.002	RIN2
positive regulation of endothelial cell migration	1	251.5×	0.007	RIN2
small GTPase-mediated signal transduction	1	183.2×	0.007	RIN2
endocytosis	1	95.2×	0.011	RIN2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
RIN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RIN2

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)
RIN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04343560	Not specified	COMPLETED	MACS and Healthy Volunteers Bone Study