RIN2

Summary

RIN2 (Ras and Rab interactor 2, HGNC:18750) is a protein-coding gene on chromosome 20p11.23, encoding Ras and Rab interactor 2 (Q8WYP3). Ras effector protein.

The RAB5 protein is a small GTPase involved in membrane trafficking in the early endocytic pathway. The protein encoded by this gene binds the GTP-bound form of the RAB5 protein preferentially over the GDP-bound form, and functions as a guanine nucleotide exchange factor for RAB5. The encoded protein is found primarily as a tetramer in the cytoplasm and does not bind other members of the RAB family. Mutations in this gene cause macrocephaly alopecia cutis laxa and scoliosis (MACS) syndrome, an elastic tissue disorder, as well as the related connective tissue disorder, RIN2 syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 54453 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RIN2 syndrome (Definitive, ClinGen)
• GWAS associations: 19
• Clinical variants (ClinVar): 788 total — 12 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 57
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_018993

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18750
Approved symbol	RIN2
Name	Ras and Rab interactor 2
Location	20p11.23
Locus type	gene with protein product
Status	Approved
Aliases	RASSF4
Ensembl gene	ENSG00000132669
Ensembl biotype	protein_coding
OMIM	610222
Entrez	54453

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 18 protein_coding, 10 protein_coding_CDS_not_defined

ENST00000255006, ENST00000412571, ENST00000426012, ENST00000432334, ENST00000440354, ENST00000459721, ENST00000465815, ENST00000467569, ENST00000484638, ENST00000488077, ENST00000616029, ENST00000648165, ENST00000648440, ENST00000891327, ENST00000891328, ENST00000891329, ENST00000944192, ENST00000944193, ENST00000944194, ENST00000944195, ENST00000944196, ENST00000944197, ENST00000944198, ENST00000944199, ENST00000944200, ENST00000944201, ENST00000944202, ENST00000944203

RefSeq mRNA: 3 — MANE Select: NM_018993 NM_001242581, NM_001378238, NM_018993

CCDS: CCDS93018

Canonical transcript exons

ENST00000255006 — 13 exons

Exon	Start	End
ENSE00001680189	19799622	19799747
ENSE00003474170	19992168	19992299
ENSE00003475492	19935099	19935199
ENSE00003480822	19990006	19990311
ENSE00003495685	19970838	19970929
ENSE00003504597	19964952	19965024
ENSE00003543272	19956615	19956807
ENSE00003591563	19960700	19960811
ENSE00003596037	19996679	19996842
ENSE00003602839	19889566	19889658
ENSE00003660467	19974654	19975787
ENSE00003840398	20000613	20002456
ENSE00003914819	19758258	19758327

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.0420 / max 968.0288, expressed in 1619 samples.

FANTOM5 promoters (31 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183738	9.1123	510
183756	6.7072	1072
183724	4.6007	637
183755	3.2648	1035
183711	2.0280	951
183753	1.7919	808
183715	1.5520	836
183757	1.4971	739
183713	1.3027	672
183722	1.2985	357

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	98.48	gold quality
tendon of biceps brachii	UBERON:0008188	98.25	gold quality
hair follicle	UBERON:0002073	98.18	gold quality
parotid gland	UBERON:0001831	98.08	gold quality
calcaneal tendon	UBERON:0003701	97.93	gold quality
decidua	UBERON:0002450	97.82	gold quality
mammary duct	UBERON:0001765	97.77	gold quality
visceral pleura	UBERON:0002401	97.63	gold quality
epithelium of mammary gland	UBERON:0003244	97.60	gold quality
synovial joint	UBERON:0002217	97.57	gold quality
tendon	UBERON:0000043	97.43	gold quality
layer of synovial tissue	UBERON:0007616	97.01	gold quality
germinal epithelium of ovary	UBERON:0001304	96.80	gold quality
skin of hip	UBERON:0001554	96.75	gold quality
pleura	UBERON:0000977	96.65	gold quality
type B pancreatic cell	CL:0000169	96.60	gold quality
caput epididymis	UBERON:0004358	96.51	gold quality
seminal vesicle	UBERON:0000998	96.33	gold quality
bronchial epithelial cell	CL:0002328	96.32	gold quality
epithelial cell of pancreas	CL:0000083	96.31	gold quality
parietal pleura	UBERON:0002400	96.07	gold quality
pericardium	UBERON:0002407	96.05	gold quality
mammalian vulva	UBERON:0000997	96.02	gold quality
gingiva	UBERON:0001828	96.01	gold quality
stromal cell of endometrium	CL:0002255	96.00	gold quality
tongue squamous epithelium	UBERON:0006919	95.97	gold quality
upper leg skin	UBERON:0004262	95.93	gold quality
palpebral conjunctiva	UBERON:0001812	95.87	gold quality
urethra	UBERON:0000057	95.84	gold quality
gingival epithelium	UBERON:0001949	95.77	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	15.83
E-MTAB-6678	yes	11.38
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

122 targeting RIN2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-7152-3P	99.97	67.47	849

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. (PMID:19631308)
• These findings confirm that RIN2 defects are associated with a distinct genodermatosis and underscore the involvement of RIN2 and its associated pathways in the pathogenesis of connective tissue disorders. (PMID:20424861)
• We describe the fourth family with RIN2 syndrome in two siblings with a novel homozygous mutation in the RIN2 gene and exhibiting additional clinical features that may also contribute to further delineation of the phenotypic spectrum. (PMID:24449201)
• we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. (PMID:27277385)
• Rab5 as a novel regulator of calpain2 activity and focal adhesion proteolysis leading to cell migration (PMID:29099266)
• Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum. (PMID:30769224)
• The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during angiogenesis. (PMID:33983539)
• Rare adult pilocytic astrocytoma of the septum pellucidum with novel RIN2::BRAF fusion. (PMID:36520196)
• NAA20 recruits Rin2 and promotes triple-negative breast cancer progression by regulating Rab5A-mediated activation of EGFR signaling. (PMID:37827343)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	rin2a	ENSDARG00000074589
danio_rerio	rin2b	ENSDARG00000077040
mus_musculus	Rin2	ENSMUSG00000001768
rattus_norvegicus	Rin2	ENSRNOG00000010131
drosophila_melanogaster	spri	FBGN0085443
drosophila_melanogaster	Rabex-5	FBGN0262937
caenorhabditis_elegans		WBGENE00008183
caenorhabditis_elegans		WBGENE00012644

Paralogs (6): VPS9D1 (ENSG00000075399), RIN3 (ENSG00000100599), RABGEF1 (ENSG00000154710), GAPVD1 (ENSG00000165219), RIN1 (ENSG00000174791), RINL (ENSG00000187994)

Protein

Protein identifiers

Ras and Rab interactor 2 — Q8WYP3 (reviewed: Q8WYP3)

Alternative names: Ras association domain family 4, Ras inhibitor JC265, Ras interaction/interference protein 2

All UniProt accessions (2): Q8WYP3, E7EPJ1

UniProt curated annotations — full annotation on UniProt →

Function. Ras effector protein. May function as an upstream activator and/or downstream effector for RAB5B in endocytic pathway. May function as a guanine nucleotide exchange (GEF) of RAB5B, required for activating the RAB5 proteins by exchanging bound GDP for free GTP.

Subunit / interactions. Homotetramer; probably composed of anti-parallel linkage of two parallel dimers. Interacts with Ras. Interacts with RAB5B, with a much higher affinity for GTP-bound activated RAB5B. Does not interact with other members of the Rab family.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Expressed in heart, kidney, lung placenta. Expressed at low level in skeletal muscle, spleen and peripheral blood.

Disease relevance. MACS syndrome (MACS) [MIM:613075] A complex disorder of elastic tissue characterized by sagging skin and occasionally by life-threatening visceral complications. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RIN (Ras interaction/interference) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WYP3-1	1	yes
Q8WYP3-2	2

RefSeq proteins (3): NP_001229510, NP_001365167, NP_061866* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR000980	SH2	Domain
IPR003123	VPS9	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035868	RIN2_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR037191	VPS9_dom_sf	Homologous_superfamily
IPR045046	Vps9-like	Family

Pfam: PF00788, PF02204, PF23268

UniProt features (17 total): domain 3, modified residue 3, region of interest 3, compositionally biased region 3, sequence variant 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYP3-F1	64.30	0.22

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 366, 501, 509

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 646 (showing top): CREL_01, GOBP_REGULATION_OF_VASCULOGENESIS, ZHAN_MULTIPLE_MYELOMA_MF_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, KYNG_DNA_DAMAGE_DN, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, ATGCAGT_MIR217, REACTOME_MEMBRANE_TRAFFICKING, GOMF_GTPASE_BINDING, CTATGCA_MIR153

GO Biological Process (7): endocytosis (GO:0006897), small GTPase-mediated signal transduction (GO:0007264), positive regulation of endothelial cell migration (GO:0010595), positive regulation of endothelial cell-matrix adhesion (GO:1904906), positive regulation of vasculogenesis (GO:2001214), signal transduction (GO:0007165), vesicle-mediated transport (GO:0016192)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), GTPase regulator activity (GO:0030695), small GTPase binding (GO:0031267)

GO Cellular Component (3): cytosol (GO:0005829), endocytic vesicle (GO:0030139), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
GTPase regulator activity	2
GTPase activity	2
cellular anatomical structure	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
intracellular signaling cassette	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
positive regulation of cell-matrix adhesion	1
endothelial cell-matrix adhesion	1
regulation of endothelial cell-matrix adhesion	1
vasculogenesis	1
positive regulation of cell differentiation	1
regulation of vasculogenesis	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transport	1
GTP binding	1
GDP binding	1
enzyme activator activity	1
nucleoside-triphosphatase regulator activity	1
GTPase binding	1
cytoplasm	1
cytoplasmic vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIN2	RAB5A	P20339	938
RIN2	RAB5B	P35239	849
RIN2	FBLN5	Q9UBX5	778
RIN2	ATP6V0A2	Q9Y487	609
RIN2	BIN1	O00499	607
RIN2	GORAB	Q5T7V8	587
RIN2	SLC67A1	Q96BI1	580
RIN2	RABIF	P47224	578
RIN2	ALDH18A1	P54886	549
RIN2	CRNKL1	Q9BZJ0	506
RIN2	TM9SF2	Q99805	490
RIN2	ZNF821	O75541	471
RIN2	ATP6V1A	P38606	455
RIN2	PIGR	P01833	454
RIN2	ERBB2	P04626	441

IntAct

11 interactions, top by confidence:

A	B	Type	Score
HRAS	RIN1	psi-mi:“MI:0914”(association)	0.930
NRAS	RAF1	psi-mi:“MI:0914”(association)	0.930
NRAS	RGL2	psi-mi:“MI:0914”(association)	0.550
ARC	FER	psi-mi:“MI:0914”(association)	0.530
RIN2	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
RIN2	EGFR	psi-mi:“MI:0407”(direct interaction)	0.440
GKAP1	RIN2	psi-mi:“MI:0915”(physical association)	0.400
CDKN2A	ACTN4	psi-mi:“MI:0914”(association)	0.350
ANKS1B	MCC	psi-mi:“MI:0914”(association)	0.350
RIN2	NAA10	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): NAA11 (Affinity Capture-MS), NAA10 (Affinity Capture-MS), RIN2 (Affinity Capture-RNA), RIN2 (Affinity Capture-MS), RIN2 (Affinity Capture-RNA), RIN2 (Affinity Capture-RNA), RIN2 (Two-hybrid), RAB5B (Two-hybrid), RAB5B (Reconstituted Complex), RIN2 (Co-purification), RIN2 (Affinity Capture-Western), NAA11 (Affinity Capture-MS), NAA10 (Affinity Capture-MS), RIN2 (Affinity Capture-MS), RIN2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: O74396, P54787, Q10NQ3, Q8TB24, Q8WYP3, Q9D684, Q9JM13, Q9LT31, A2RV61, A5D794, P59729, P97680, Q13671, Q14C86, Q6PAR5, Q6ZS11, Q80UW3, Q921Q7, O18973, Q8MQW8, Q9UJ41, A8WVM4, Q29HW3, Q9VZ08, Q9GYH7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF/MAP kinase cascade	5	27.8×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

788 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	6
Uncertain significance	373
Likely benign	270
Benign	48

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1073862	NM_018993.4(RIN2):c.2272C>T (p.Arg758Ter)	Pathogenic
1296	NM_018993.4(RIN2):c.1731del (p.Ile578fs)	Pathogenic
137627	NM_018993.4(RIN2):c.1731dup (p.Ile578fs)	Pathogenic
1956833	NM_018993.4(RIN2):c.46del (p.Ser16fs)	Pathogenic
2127246	NM_018993.4(RIN2):c.814_826del (p.Ile272fs)	Pathogenic
2751044	NM_018993.4(RIN2):c.97C>T (p.Gln33Ter)	Pathogenic
2793456	NM_018993.4(RIN2):c.131del (p.Asn44fs)	Pathogenic
3645796	NM_018993.4(RIN2):c.1916dup (p.Val641fs)	Pathogenic
3663530	NM_018993.4(RIN2):c.921_922insG (p.Pro308fs)	Pathogenic
36923	NM_018993.4(RIN2):c.1914_1915del (p.Glu638fs)	Pathogenic
4728187	NM_018993.4(RIN2):c.462C>G (p.Tyr154Ter)	Pathogenic
4733666	NM_018993.4(RIN2):c.183del (p.Tyr62fs)	Pathogenic
2760409	NM_018993.4(RIN2):c.2069-1G>T	Likely pathogenic
2771606	NM_018993.4(RIN2):c.537-2A>C	Likely pathogenic
3346911	NM_018993.4(RIN2):c.351+2T>A	Likely pathogenic
3769812	NM_018993.4(RIN2):c.277del (p.Thr93fs)	Likely pathogenic
590794	NM_018993.4(RIN2):c.2104dup (p.Leu702fs)	Likely pathogenic
804430	NM_018993.4(RIN2):c.277_278dup (p.His94fs)	Likely pathogenic

SpliceAI

4672 predictions. Top by Δscore:

Variant	Effect	Δscore
10:44959864:ACGG:A	donor_loss	1.0000
10:44959865:CGG:C	donor_loss	1.0000
10:44959866:GGT:G	donor_loss	1.0000
10:44959867:GTGA:G	donor_loss	1.0000
10:44970262:G:GT	donor_gain	1.0000
10:44970262:GAA:G	donor_gain	1.0000
10:44970265:G:GG	donor_gain	1.0000
10:44971767:TTTTA:T	acceptor_loss	1.0000
10:44971768:TTTAG:T	acceptor_loss	1.0000
10:44971769:TTA:T	acceptor_loss	1.0000
10:44971770:TAG:T	acceptor_loss	1.0000
10:44971772:G:A	acceptor_loss	1.0000
10:44971846:GAGGT:G	donor_loss	1.0000
10:44971848:GGTG:G	donor_loss	1.0000
10:44971849:GTGAG:G	donor_loss	1.0000
10:44971850:T:G	donor_loss	1.0000
10:44978055:CCTG:C	acceptor_loss	1.0000
10:44978615:TACC:T	donor_loss	1.0000
10:44978617:C:CT	donor_loss	1.0000
10:44984808:T:G	acceptor_gain	1.0000
10:44984811:A:AG	acceptor_gain	1.0000
10:44984811:AG:A	acceptor_gain	1.0000
10:44984812:G:GT	acceptor_gain	1.0000
10:44984812:GG:G	acceptor_gain	1.0000
10:44984966:ATAAG:A	donor_loss	1.0000
10:44984967:TAAG:T	donor_loss	1.0000
10:44984968:AAG:A	donor_loss	1.0000
10:44984969:AGGTG:A	donor_loss	1.0000
10:44984970:GG:G	donor_loss	1.0000
10:44984971:GTGAT:G	donor_loss	1.0000

AlphaMissense

6217 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:19956745:T:A	W97R	1.000
20:19956745:T:C	W97R	1.000
20:19964981:T:C	F165L	1.000
20:19964983:C:A	F165L	1.000
20:19964983:C:G	F165L	1.000
20:19965000:T:C	L171P	1.000
20:19992192:T:C	F698S	1.000
20:19992204:T:C	L702P	1.000
20:19992270:T:C	L724P	1.000
20:19996684:T:C	Y736H	1.000
20:20000626:T:A	V793D	1.000
20:19956725:T:C	L90P	0.999
20:19956749:T:C	L98P	0.999
20:19960710:T:A	V121D	0.999
20:19960794:T:A	I149K	0.999
20:19965008:T:C	F174L	0.999
20:19965010:C:A	F174L	0.999
20:19965010:C:G	F174L	0.999
20:19965020:A:C	S178R	0.999
20:19965022:C:A	S178R	0.999
20:19965022:C:G	S178R	0.999
20:19965024:G:T	R179M	0.999
20:19970846:T:A	L182Q	0.999
20:19970846:T:C	L182P	0.999
20:19970858:T:C	L186S	0.999
20:19970858:T:G	L186W	0.999
20:19975613:G:T	G530W	0.999
20:19975614:G:A	G530E	0.999
20:19975698:G:C	R558P	0.999
20:19975728:T:C	L568S	0.999

dbSNP variants (sampled 300 via entrez): RS1000002412 (20:19904696 A>G), RS1000002736 (20:19802422 G>A,T), RS1000018835 (20:19861244 C>A,G), RS1000038201 (20:19825456 T>C), RS1000049012 (20:19901834 T>C), RS1000049713 (20:19836310 T>A), RS1000052544 (20:19867661 G>C), RS1000064448 (20:19995073 T>A,G), RS1000075784 (20:19994775 C>G), RS1000096177 (20:19817174 A>G), RS1000105192 (20:19914474 A>G,T), RS1000111193 (20:19983747 G>A,T), RS1000127454 (20:19890506 C>T), RS1000137839 (20:19914301 T>G), RS1000139415 (20:19904463 G>A,T)

Disease associations

OMIM: gene MIM:610222 | disease phenotypes: MIM:613075

GenCC curated gene-disease

Disease	Classification	Inheritance
RIN2 syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
RIN2 syndrome	Definitive	AR

Mondo (1): RIN2 syndrome (MONDO:0013115)

Orphanet (1): RIN2 syndrome (Orphanet:217335)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000159	Abnormal lip morphology
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000431	Wide nasal bridge
HP:0000494	Downslanted palpebral fissures
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000815	Hypergonadotropic hypogonadism
HP:0000939	Osteoporosis
HP:0000954	Single transverse palmar crease
HP:0000973	Cutis laxa
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0001007	Hirsutism
HP:0001156	Brachydactyly
HP:0001252	Hypotonia
HP:0001382	Joint hypermobility
HP:0001537	Umbilical hernia
HP:0001582	Redundant skin
HP:0001596	Alopecia
HP:0001620	Abnormally high-pitched voice

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000821_62	Bipolar disorder and schizophrenia	4.000000e-07
GCST001762_191	Obesity-related traits	5.000000e-06
GCST002701_29	Verbal declarative memory	2.000000e-06
GCST004616_152	Platelet distribution width	3.000000e-17
GCST006143_11	Bone mineral density (total hip)	6.000000e-06
GCST007327_84	Smoking status (ever vs never smokers)	6.000000e-10
GCST008141_7	HDL cholesterol	4.000000e-06
GCST008152_136	Weight	6.000000e-06
GCST009391_1389	Metabolite levels	6.000000e-06
GCST009391_18	Metabolite levels	2.000000e-06
GCST009545_2	Moderate or severe prolonged lymphopenia in dimethyl fumarate-treated relapsing-remitting multiple sclerosis	1.000000e-06
GCST010266_16	Femoral neck bone mineral density and trunk fat mass adjusted by trunk lean mass	9.000000e-07
GCST010267_3	Trunk fat mass adjusted for trunk lean mass	9.000000e-09
GCST010295_3	Response to valproic acid in genetic generalized epilepsy	7.000000e-06
GCST90002401_313	Platelet distribution width	4.000000e-15
GCST90002401_314	Platelet distribution width	4.000000e-57
GCST90002401_315	Platelet distribution width	2.000000e-25
GCST90002401_316	Platelet distribution width	2.000000e-09
GCST90002401_317	Platelet distribution width	5.000000e-12

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0007984	platelet component distribution width
EFO:0007702	hip bone mineral density
EFO:0004318	smoking behavior
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004338	body weight
EFO:0010368	lysophosphatidylethanolamine 18:1 measurement
EFO:0007785	femoral neck bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567770	Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression, increases expression, increases methylation	6
Cyclosporine	affects expression, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
entinostat	affects cotreatment, decreases expression	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tretinoin	increases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
salinomycin	decreases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium bichromate	decreases expression	1
cobaltous chloride	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Zoledronic Acid	affects cotreatment, increases expression	1
Fluvastatin	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Azathioprine	increases expression	1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

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