RASSF4

Summary

RASSF4 (Ras association domain family member 4, HGNC:20793) is a protein-coding gene on chromosome 10q11.21, encoding Ras association domain-containing protein 4 (Q9H2L5). Potential tumor suppressor.

The function of this gene has not yet been determined but may involve a role in tumor suppression. Alternative splicing of this gene results in several transcript variants; however, most of the variants have not been fully described.

Source: NCBI Gene 83937 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_032023

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20793
Approved symbol	RASSF4
Name	Ras association domain family member 4
Location	10q11.21
Locus type	gene with protein product
Status	Approved
Aliases	AD037, MGC44914
Ensembl gene	ENSG00000107551
Ensembl biotype	protein_coding
OMIM	610559
Entrez	83937

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 17 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000340258, ENST00000427758, ENST00000428466, ENST00000462822, ENST00000465735, ENST00000471808, ENST00000471941, ENST00000472561, ENST00000483709, ENST00000484477, ENST00000489171, ENST00000493490, ENST00000891515, ENST00000891516, ENST00000891517, ENST00000891518, ENST00000891519, ENST00000952757, ENST00000952758, ENST00000952759, ENST00000952760, ENST00000952761, ENST00000952762, ENST00000952763, ENST00000952764

RefSeq mRNA: 1 — MANE Select: NM_032023 NM_032023

CCDS: CCDS7208

Canonical transcript exons

ENST00000340258 — 11 exons

Exon	Start	End
ENSE00001922035	44993269	44995891
ENSE00001952398	44959802	44959866
ENSE00003231874	44970165	44970264
ENSE00003520204	44984813	44984970
ENSE00003532689	44971773	44971848
ENSE00003544384	44989274	44989375
ENSE00003545929	44982521	44982663
ENSE00003564870	44991905	44992002
ENSE00003574745	44990948	44991069
ENSE00003587639	44984022	44984113
ENSE00003708570	44989670	44989721

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.7588 / max 890.1899, expressed in 1396 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104775	31.7076	1370
104776	0.0511	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	98.67	gold quality
left lobe of thyroid gland	UBERON:0001120	98.45	gold quality
thyroid gland	UBERON:0002046	97.73	gold quality
granulocyte	CL:0000094	97.00	gold quality
monocyte	CL:0000576	96.77	gold quality
mononuclear cell	CL:0000842	96.50	gold quality
apex of heart	UBERON:0002098	96.42	gold quality
tibial nerve	UBERON:0001323	96.31	gold quality
leukocyte	CL:0000738	96.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.91	gold quality
metanephros cortex	UBERON:0010533	95.34	gold quality
spinal cord	UBERON:0002240	94.96	gold quality
medial globus pallidus	UBERON:0002477	94.92	gold quality
right atrium auricular region	UBERON:0006631	94.80	gold quality
globus pallidus	UBERON:0001875	94.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.51	gold quality
heart left ventricle	UBERON:0002084	94.36	gold quality
amygdala	UBERON:0001876	94.26	gold quality
right frontal lobe	UBERON:0002810	94.23	gold quality
adult mammalian kidney	UBERON:0000082	94.13	gold quality
body of pancreas	UBERON:0001150	94.09	gold quality
cardiac ventricle	UBERON:0002082	94.05	gold quality
cerebellar hemisphere	UBERON:0002245	94.02	gold quality
left coronary artery	UBERON:0001626	94.01	gold quality
cerebellar cortex	UBERON:0002129	93.85	gold quality
coronary artery	UBERON:0001621	93.79	gold quality
caudate nucleus	UBERON:0001873	93.73	gold quality
spleen	UBERON:0002106	93.51	gold quality
lateral globus pallidus	UBERON:0002476	93.50	gold quality
cardiac atrium	UBERON:0002081	93.42	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	3437.96
E-CURD-119	yes	53.69
E-MTAB-6701	yes	43.67
E-MTAB-6678	yes	40.62
E-MTAB-7316	yes	26.02
E-HCAD-11	yes	24.00
E-CURD-112	yes	21.77
E-CURD-122	yes	21.41
E-CURD-46	yes	15.86
E-MTAB-9067	yes	10.27
E-MTAB-9801	yes	6.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting RASSF4, 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-4283	100.00	66.42	2097
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-4297	98.77	66.95	2013

Literature-anchored findings (GeneRIF, showing 9)

• Single nucleotide polymorphism in RASSF4 gene is associated with acute lymphoblastic leukemia. (PMID:19066393)
• expression of SPRR1B is upregulated in oral CSCs/CICs and SPRR1B has a role in cell growth by suppression of RASSF4 (PMID:23954638)
• RASSF4 promotes EV71 replication and the production of viral progeny to accelerate the inhibition of the phosphorylation of AKT. (PMID:25701784)
• the present study suggested that RASSF4 serves as an important tumor suppressor in human nonsmall cell lung cancer . (PMID:26526576)
• RASSF4 overexpression inhibits proliferation, invasion, EMT, and Wnt signaling pathway in osteosarcoma cells. (PMID:28081736)
• RASSF4 controls store operated calcium entry and endoplasmic reticulum-plasma membrane junctions through ARF6-dependent regulation of PM PI(4,5)P2 levels, pivotal for a variety of physiological processes. (PMID:28600435)
• Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression. (PMID:29259009)
• RASSF4 is required for skeletal muscle differentiation. (PMID:31508857)
• Wnt/beta-catenin signaling pathway participates in the effect of miR-626 on oral squamous cell carcinoma by targeting RASSF4. (PMID:34121238)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rassf4a	ENSDARG00000012460
danio_rerio	RASSF4	ENSDARG00000112861
mus_musculus	Rassf4	ENSMUSG00000042129
rattus_norvegicus	Rassf4	ENSRNOG00000013526
drosophila_melanogaster	Rassf	FBGN0039055

Paralogs (5): RASSF1 (ENSG00000068028), RASSF2 (ENSG00000101265), RASSF3 (ENSG00000153179), RASSF6 (ENSG00000169435), RASSF5 (ENSG00000266094)

Protein

Protein identifiers

Ras association domain-containing protein 4 — Q9H2L5 (reviewed: Q9H2L5)

All UniProt accessions (5): Q9H2L5, Q5T737, Q5T739, R4GNA4, V9GYK1

UniProt curated annotations — full annotation on UniProt →

Function. Potential tumor suppressor. May act as a KRAS effector protein. May promote apoptosis and cell cycle arrest.

Subunit / interactions. Interacts directly with activated KRAS in a GTP-dependent manner.

Tissue specificity. Widely expressed. Frequently down-regulated in tumor cell lines.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9H2L5-1	1, A	yes
Q9H2L5-2	2, C
Q9H2L5-3	3, B
Q9H2L5-4	4, D

RefSeq proteins (1): NP_114412* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR011524	SARAH_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR033614	RASSF1-6	Family
IPR033622	RASSF4_RA	Domain

Pfam: PF00788, PF16517

UniProt features (14 total): splice variant 5, domain 2, sequence variant 2, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2L5-F1	78.51	0.59

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 (1): 141

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): ZHAN_MULTIPLE_MYELOMA_MF_UP, CTATGCA_MIR153, CHANDRAN_METASTASIS_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, VALK_AML_CLUSTER_5, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, GRYDER_PAX3FOXO1_TOP_ENHANCERS, LEIN_PONS_MARKERS, LEIN_MEDULLA_MARKERS, SANSOM_APC_TARGETS

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
binding	1

Protein interactions and networks

STRING

390 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RASSF4	PLPBP	O94903	455
RASSF4	LRRC59	Q96AG4	446
RASSF4	RASSF7	Q02833	434
RASSF4	RASSF8	Q8NHQ8	393
RASSF4	CYB5D1	Q6P9G0	369
RASSF4	RASSF10	A6NK89	349
RASSF4	LRFN2	Q9ULH4	345
RASSF4	TMEM178A	Q8NBL3	343
RASSF4	RASSF9	O75901	340
RASSF4	EPHX1	P07099	323
RASSF4	SYVN1	Q86TM6	322
RASSF4	SPRR1B	P22528	315
RASSF4	STIMATE	Q86TL2	303
RASSF4	CDA	P32320	298
RASSF4	TM9SF1	O15321	287

IntAct

37 interactions, top by confidence:

A	B	Type	Score
STK3	RASSF2	psi-mi:“MI:0914”(association)	0.950
RASSF4	STK3	psi-mi:“MI:0915”(physical association)	0.900
STK3	RASSF4	psi-mi:“MI:0915”(physical association)	0.900
STK4	RASSF4	psi-mi:“MI:0915”(physical association)	0.830
RASSF4	STK4	psi-mi:“MI:0915”(physical association)	0.830
RASSF4	STK4	psi-mi:“MI:0914”(association)	0.830
STK4	MAP1B	psi-mi:“MI:0914”(association)	0.730
MAGEA6	RASSF4	psi-mi:“MI:0915”(physical association)	0.720
STK4	STRN	psi-mi:“MI:0914”(association)	0.610
HGS	RASSF4	psi-mi:“MI:0915”(physical association)	0.560
IFT20	RASSF4	psi-mi:“MI:0915”(physical association)	0.560
RASSF4	CENPH	psi-mi:“MI:0915”(physical association)	0.560
RASSF4	DLG4	psi-mi:“MI:0915”(physical association)	0.370
RASSF4	SAV1	psi-mi:“MI:0915”(physical association)	0.370
RASSF3	RASSF4	psi-mi:“MI:0915”(physical association)	0.370
RASSF4	RASSF5	psi-mi:“MI:0915”(physical association)	0.370
STK3	NEB	psi-mi:“MI:0914”(association)	0.350
STK3	THAP12	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): RASSF4 (Two-hybrid), RASSF4 (Two-hybrid), RASSF4 (Affinity Capture-MS), STK4 (Affinity Capture-MS), STK3 (Affinity Capture-MS), RASSF4 (Two-hybrid), IFT20 (Two-hybrid), CENPH (Two-hybrid), HGS (Two-hybrid), MAGEA6 (Two-hybrid), RASSF4 (Two-hybrid), RASSF4 (Affinity Capture-MS), EIF5B (Cross-Linking-MS (XL-MS)), EIF5B (Cross-Linking-MS (XL-MS)), RASSF4 (Affinity Capture-MS)

ESM2 similar proteins: A2A2Y4, A2AFR3, A4IJ06, B9EJ86, E1C3P4, F1LXF1, G9CGD6, O08874, O14795, P49797, Q05AA6, Q0P4Q4, Q0VGY8, Q13474, Q14CM0, Q16513, Q3B7D5, Q566C5, Q5F3L9, Q5R803, Q62769, Q641K1, Q69ZK0, Q6DRP4, Q6NTL4, Q6PAJ1, Q6ZM86, Q7Z628, Q80TI0, Q8BHD4, Q8BMS9, Q8C0V9, Q8CB96, Q8IZC4, Q8K2Y9, Q8TCU6, Q923Q2, Q92625, Q96NE9, Q9BSQ5

Diamond homologs: P50749, Q3B7D5, Q4QR82, Q566C5, Q5EBH1, Q6ZTQ3, Q80UQ2, Q8BMS9, Q8CB96, Q9H2L5, Q99MK9, Q9NS23, O35141, Q22744, Q86WH2, Q8WWW0, Q99P51, Q9R1K8, Q9Z1S3, A4IJ06, A8KBH6, A8XQD5, D3ZEY4, O45818, O94806, O95267, P04409, P05126, P05128, P05129, P05696, P05771, P05772, P09215, P09216, P10102, P10829, P10830, P13677, P13678

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:44989283:T:C	F181L	0.999
10:44989285:T:A	F181L	0.999
10:44989285:T:G	F181L	0.999
10:44982563:T:A	W61R	0.998
10:44982563:T:C	W61R	0.998
10:44989370:T:C	F210L	0.998
10:44989372:T:A	F210L	0.998
10:44989372:T:G	F210L	0.998
10:44989284:T:C	F181S	0.997
10:44982545:G:A	G55R	0.996
10:44982545:G:C	G55R	0.996
10:44982565:G:C	W61C	0.996
10:44982565:G:T	W61C	0.996
10:44989325:A:C	S195R	0.996
10:44989327:C:A	S195R	0.996
10:44989327:C:G	S195R	0.996
10:44982545:G:T	G55W	0.995
10:44984959:T:G	Y174D	0.995
10:44989691:T:C	F219L	0.995
10:44989693:C:A	F219L	0.995
10:44989693:C:G	F219L	0.995
10:44989284:T:G	F181C	0.994
10:44989290:C:A	P183Q	0.994
10:44989368:A:T	K209I	0.994
10:44991939:T:C	L281P	0.994
10:44971801:T:G	Y31D	0.993
10:44982546:G:A	G55E	0.993
10:44982552:T:C	L57P	0.993
10:44991960:T:C	L288S	0.993
10:44989320:T:A	V193D	0.992

dbSNP variants (sampled 300 via entrez): RS1000016528 (10:44994275 C>A), RS1000084765 (10:44995747 A>C), RS1000182403 (10:44961170 C>G), RS1000297914 (10:44991335 T>A,C), RS1000366651 (10:44967380 C>T), RS1000557444 (10:44994569 T>C), RS1000592491 (10:44960019 G>T), RS1000659000 (10:44961483 G>A), RS1000699398 (10:44965908 C>T), RS1000799663 (10:44985920 T>C), RS1000921387 (10:44959769 A>G,T), RS1000978197 (10:44963484 C>T), RS1001055039 (10:44975090 G>A), RS1001055685 (10:44975365 C>CA), RS1001161369 (10:44975959 T>C)

Disease associations

OMIM: gene MIM:610559 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
Cyclosporine	decreases expression	3
sodium arsenite	affects methylation, decreases expression	2
Dexamethasone	affects cotreatment, increases expression	2
Nickel	increases expression	2
Smoke	decreases expression, increases abundance	2
Tretinoin	increases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
gardiquimod	increases expression, decreases reaction	1
(+)-JQ1 compound	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7Z7	Ubigene A-549 RASSF4 KO	Cancer cell line	Male
CVCL_D8UF	Ubigene HCT 116 RASSF4 KO	Cancer cell line	Male
CVCL_XS14	HAP1 RASSF4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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