FRMD4B

Summary

FRMD4B (FERM domain containing 4B, HGNC:24886) is a protein-coding gene on chromosome 3p14.1, encoding FERM domain-containing protein 4B (Q9Y2L6). Member of GRP1 signaling complexes that are acutely recruited to plasma membrane ruffles in response to insulin receptor signaling.

This gene encodes a GRP1-binding protein which contains a FERM protein interaction domain as well as two coiled coil domains. This protein may play a role as a scaffolding protein.

Source: NCBI Gene 23150 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 184 total
• MANE Select transcript: NM_015123

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24886
Approved symbol	FRMD4B
Name	FERM domain containing 4B
Location	3p14.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1013, GRSP1
Ensembl gene	ENSG00000114541
Ensembl biotype	protein_coding
OMIM	617467
Entrez	23150

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 10 protein_coding, 5 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000398540, ENST00000459638, ENST00000460709, ENST00000462308, ENST00000462512, ENST00000462888, ENST00000470070, ENST00000473029, ENST00000473188, ENST00000478263, ENST00000483668, ENST00000487751, ENST00000489817, ENST00000493127, ENST00000493880, ENST00000497475, ENST00000497757, ENST00000497880, ENST00000863518

RefSeq mRNA: 1 — MANE Select: NM_015123 NM_015123

CCDS: CCDS46863

Canonical transcript exons

ENST00000398540 — 23 exons

Exon	Start	End
ENSE00001149203	69168782	69171981
ENSE00001175437	69176524	69176656
ENSE00001175443	69180899	69181710
ENSE00001175454	69182598	69182717
ENSE00001175465	69187770	69187917
ENSE00001175474	69189896	69189952
ENSE00001175482	69193648	69193873
ENSE00001697213	69195022	69195141
ENSE00001699364	69196255	69196396
ENSE00001725123	69195231	69195364
ENSE00001840385	69385828	69386088
ENSE00003475493	69198698	69198774
ENSE00003500809	69302343	69302435
ENSE00003547599	69311263	69311357
ENSE00003576743	69218322	69218379
ENSE00003582902	69249226	69249248
ENSE00003620920	69196900	69197038
ENSE00003620942	69250043	69250099
ENSE00003628002	69221858	69221923
ENSE00003636720	69287752	69287836
ENSE00003758870	69313452	69313517
ENSE00003787893	69216263	69216349
ENSE00003789462	69224607	69224690

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6930 / max 475.2904, expressed in 1208 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42997	3.7712	563
42964	1.9312	362
42971	1.7103	426
42978	1.3299	218
42975	1.2851	377
42995	0.8621	292
42973	0.6595	257
42998	0.5418	231
42976	0.4592	224
42982	0.3188	126

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	97.08	gold quality
calcaneal tendon	UBERON:0003701	96.45	gold quality
cortical plate	UBERON:0005343	96.38	gold quality
sural nerve	UBERON:0015488	96.20	gold quality
esophagus squamous epithelium	UBERON:0006920	95.96	gold quality
corpus callosum	UBERON:0002336	95.90	gold quality
oral cavity	UBERON:0000167	94.97	gold quality
ganglionic eminence	UBERON:0004023	94.66	gold quality
squamous epithelium	UBERON:0006914	94.40	gold quality
tongue squamous epithelium	UBERON:0006919	93.87	gold quality
parietal pleura	UBERON:0002400	93.58	gold quality
palpebral conjunctiva	UBERON:0001812	93.42	gold quality
inferior vagus X ganglion	UBERON:0005363	93.24	gold quality
epithelium of esophagus	UBERON:0001976	93.21	gold quality
pleura	UBERON:0000977	92.63	gold quality
gingival epithelium	UBERON:0001949	92.45	gold quality
right lobe of thyroid gland	UBERON:0001119	91.99	gold quality
gingiva	UBERON:0001828	91.94	gold quality
subthalamic nucleus	UBERON:0001906	91.87	gold quality
thyroid gland	UBERON:0002046	91.83	gold quality
left lobe of thyroid gland	UBERON:0001120	91.62	gold quality
pharyngeal mucosa	UBERON:0000355	91.41	gold quality
synovial joint	UBERON:0002217	91.27	gold quality
parotid gland	UBERON:0001831	91.21	gold quality
cervix squamous epithelium	UBERON:0006922	91.05	gold quality
visceral pleura	UBERON:0002401	90.91	gold quality
esophagus mucosa	UBERON:0002469	90.47	gold quality
cranial nerve II	UBERON:0000941	90.31	gold quality
monocyte	CL:0000576	90.16	gold quality
right lung	UBERON:0002167	90.12	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	1796.26
E-MTAB-11268	yes	1665.06
E-HCAD-5	yes	302.77
E-HCAD-35	yes	100.05
E-HCAD-25	yes	62.56
E-ANND-3	yes	18.43
E-MTAB-6678	yes	10.53
E-GEOD-137537	yes	4.00
E-ANND-2	no	1002.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

219 targeting FRMD4B, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Literature-anchored findings (GeneRIF, showing 2)

• SNP is located in a 3’ intronic region of the FRMD4B gene. FRMD4B as novel susceptibility loci for advanced heart failure. (PMID:20124441)
• association between the intronic rs6787362 FRMD4B SNP and ischemic cardiomyopathy in a European-derived population, but not FRMD4B variants as susceptibility factors in common heart failure (PMID:20718813)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	frmd4ba	ENSDARG00000074599
danio_rerio	frmd4bb	ENSDARG00000076496
mus_musculus	Frmd4b	ENSMUSG00000030064
rattus_norvegicus	Frmd4b	ENSRNOG00000007764
caenorhabditis_elegans		WBGENE00008555

Paralogs (6): EZR (ENSG00000092820), ERMN (ENSG00000136541), RDX (ENSG00000137710), MSN (ENSG00000147065), FRMD4A (ENSG00000151474), NF2 (ENSG00000186575)

Protein

Protein identifiers

FERM domain-containing protein 4B — Q9Y2L6 (reviewed: Q9Y2L6)

Alternative names: GRP1-binding protein GRSP1

All UniProt accessions (9): C9J6Q2, C9J7M5, C9JA15, C9JAW0, C9JBX2, C9JYK2, E9PGA7, Q9Y2L6, H7C550

UniProt curated annotations — full annotation on UniProt →

Function. Member of GRP1 signaling complexes that are acutely recruited to plasma membrane ruffles in response to insulin receptor signaling. May function as a scaffolding protein that regulates epithelial cell polarity by connecting ARF6 activation with the PAR3 complex. Plays a redundant role with FRMD4A in epithelial polarization.

Subunit / interactions. Interacts with CYTH3. Interacts with PARD3. Interacts with CYTH1.

Subcellular location. Cytoplasm. Cytoskeleton. Cell junction. Tight junction. Adherens junction.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2L6-1	1	yes
Q9Y2L6-2	2

RefSeq proteins (1): NP_055938* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR021774	CUPID	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR041785	FRMD4A/B_FERM_C	Domain
IPR047176	FRMD4A/B	Family

Pfam: PF00373, PF09379, PF09380, PF11819

UniProt features (28 total): compositionally biased region 8, region of interest 7, modified residue 4, coiled-coil region 2, cross-link 2, sequence conflict 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2L6-F1	62.91	0.29

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 (6): 372, 608, 697, 915, 882, 1029

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 325 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_ESTABLISHMENT_OF_EPITHELIAL_CELL_POLARITY, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOCC_RUFFLE, BILD_SRC_ONCOGENIC_SIGNATURE, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, MARTINEZ_RB1_TARGETS_UP, ONKEN_UVEAL_MELANOMA_UP, MARTIN_VIRAL_GPCR_SIGNALING_DN, TIEN_INTESTINE_PROBIOTICS_24HR_UP, BROWNE_HCMV_INFECTION_6HR_UP

GO Biological Process (1): establishment of epithelial cell polarity (GO:0090162)

GO Molecular Function (0):

GO Cellular Component (7): ruffle (GO:0001726), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
establishment of cell polarity	1
cell leading edge	1
plasma membrane bounded cell projection	1
intracellular anatomical structure	1
cellular anatomical structure	1
intracellular membraneless organelle	1
cell-cell junction	1
apical junction complex	1
tight junction	1
cell junction	1

Protein interactions and networks

STRING

870 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRMD4B	CYTH3	O43739	862
FRMD4B	CYTH1	Q15438	855
FRMD4B	CYTH4	Q9UIA0	629
FRMD4B	CYTH2	Q99418	616
FRMD4B	HSPB7	Q9UBY9	544
FRMD4B	TMTC4	Q5T4D3	519
FRMD4B	GPA33	Q99795	461
FRMD4B	DYNLRB2	Q8TF09	433
FRMD4B	PLEKHA5	Q9HAU0	425
FRMD4B	NUSAP1	Q9BXS6	418
FRMD4B	CPNE4	Q96A23	406
FRMD4B	TMEM260	Q9NX78	398
FRMD4B	MEIG1	Q5JSS6	383
FRMD4B	CDKN2A	P42771	375
FRMD4B	ARL4A	P40617	374

IntAct

6 interactions, top by confidence:

A	B	Type	Score
FRMD4B	AFDN	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
FRMD4B	Zap70	psi-mi:“MI:0914”(association)	0.350
CYTH1	CYTH3	psi-mi:“MI:0914”(association)	0.350
	NFIB	psi-mi:“MI:0914”(association)	0.350
RSPH1	FRMD4B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): FRMD4B (Affinity Capture-MS), RNF146 (Affinity Capture-Western), FRMD4B (Affinity Capture-Luminescence), FRMD4B (Proximity Label-MS), MLLT4 (Affinity Capture-MS), FRMD4B (Affinity Capture-MS), FRMD4B (Proximity Label-MS), FRMD4B (Two-hybrid), FRMD4B (Affinity Capture-MS), FRMD4B (Affinity Capture-MS), FRMD4B (Affinity Capture-RNA)

ESM2 similar proteins: A0A0G2K2P5, A0JNJ1, B1WAP7, G9CGD6, O14640, O75122, O88382, O95049, O97758, P34908, P39447, P51141, P54792, P70175, Q05AS8, Q07157, Q16825, Q5F488, Q5IS48, Q5SGD7, Q5TCQ9, Q5XI81, Q61062, Q62136, Q62728, Q62936, Q6DKE2, Q6P9H4, Q6ZM86, Q812E4, Q86UL8, Q8BMA3, Q8IVH8, Q8JHI3, Q8TDW5, Q920B0, Q924I2, Q925T6, Q92997, Q95168

Diamond homologs: A2AEV7, Q3KP66, Q7TN12, Q920B0, Q96HB5, Q9Y2L6, A2ALK8, B0WYY2, F1LYQ8, F1P065, F8VPU2, O35763, O43491, O70318, O94887, P11171, P12264, P15311, P26038, P26040, P26041, P26042, P26043, P26044, P26045, P29074, P31976, P31977, P35240, P35241, P46150, P46662, P48193, P52962, P59750, P86232, Q12923, Q170J7, Q24564, Q29GR8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	156
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3970 predictions. Top by Δscore:

Variant	Effect	Δscore
3:69176653:GACAC:G	acceptor_loss	1.0000
3:69176654:ACACT:A	acceptor_loss	1.0000
3:69176655:CA:C	acceptor_gain	1.0000
3:69176656:ACTG:A	acceptor_loss	1.0000
3:69176657:C:A	acceptor_loss	1.0000
3:69176657:C:CC	acceptor_gain	1.0000
3:69176658:T:A	acceptor_loss	1.0000
3:69182594:TTA:T	donor_loss	1.0000
3:69182595:TACT:T	donor_loss	1.0000
3:69182596:A:AC	donor_gain	1.0000
3:69182596:A:T	donor_loss	1.0000
3:69182596:ACT:A	donor_gain	1.0000
3:69182597:C:CC	donor_gain	1.0000
3:69182597:CT:C	donor_gain	1.0000
3:69182597:CTC:C	donor_gain	1.0000
3:69182599:C:CA	donor_gain	1.0000
3:69182713:TTTCT:T	acceptor_gain	1.0000
3:69182714:TTCT:T	acceptor_gain	1.0000
3:69182718:C:CC	acceptor_gain	1.0000
3:69189894:A:AC	donor_gain	1.0000
3:69189895:C:CC	donor_gain	1.0000
3:69189895:CGAT:C	donor_gain	1.0000
3:69189953:C:CC	acceptor_gain	1.0000
3:69193646:A:T	donor_loss	1.0000
3:69193647:C:T	donor_loss	1.0000
3:69194977:T:TA	donor_gain	1.0000
3:69195020:A:AC	donor_gain	1.0000
3:69195021:C:CC	donor_gain	1.0000
3:69195021:CTT:C	donor_gain	1.0000
3:69195021:CTTCT:C	donor_gain	1.0000

AlphaMissense

6771 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:69196943:G:T	A350E	1.000
3:69196944:C:G	A350P	1.000
3:69196953:A:G	W347R	1.000
3:69196953:A:T	W347R	1.000
3:69196986:A:G	W336R	1.000
3:69196986:A:T	W336R	1.000
3:69198719:A:T	V311D	1.000
3:69198723:C:G	A310P	1.000
3:69198724:A:C	F309L	1.000
3:69198724:A:T	F309L	1.000
3:69198725:A:C	F309C	1.000
3:69198725:A:G	F309S	1.000
3:69198726:A:G	F309L	1.000
3:69198746:A:G	L302S	1.000
3:69198755:A:G	L299P	1.000
3:69198763:C:A	W296C	1.000
3:69198763:C:G	W296C	1.000
3:69198764:C:G	W296S	1.000
3:69198765:A:G	W296R	1.000
3:69198765:A:T	W296R	1.000
3:69216307:C:G	G278R	1.000
3:69216307:C:T	G278R	1.000
3:69216321:C:T	G273E	1.000
3:69216322:C:G	G273R	1.000
3:69216322:C:T	G273R	1.000
3:69216324:A:G	L272P	1.000
3:69181054:A:G	L899S	0.999
3:69195233:C:G	A456P	0.999
3:69196924:A:C	F356L	0.999
3:69196924:A:T	F356L	0.999

dbSNP variants (sampled 300 via entrez): RS1000007820 (3:69304711 T>G), RS1000008707 (3:69367413 C>T), RS1000020893 (3:69430986 C>A), RS1000026926 (3:69365567 C>T), RS1000040032 (3:69400167 C>G,T), RS1000040682 (3:69341725 G>A), RS1000045058 (3:69451176 T>A), RS1000049201 (3:69409297 T>A), RS1000049796 (3:69278590 G>C), RS1000055721 (3:69359031 C>T), RS1000084593 (3:69241957 G>A), RS1000089834 (3:69330897 G>A,T), RS1000094478 (3:69495929 A>C), RS1000115777 (3:69252398 C>T), RS1000117910 (3:69196021 C>G)

Disease associations

OMIM: gene MIM:617467 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000612_40	Celiac disease	2.000000e-07
GCST003818_26	Resting heart rate	3.000000e-15
GCST003902_1	Fast beta electroencephalogram	2.000000e-07
GCST003944_38	Hepcidin/ferritin ratio	3.000000e-06
GCST003944_39	Hepcidin/ferritin ratio	8.000000e-06
GCST006138_40	Resting-state electroencephalogram vigilance	8.000000e-06
GCST006414_78	Atrial fibrillation	3.000000e-09
GCST007045_21	PR interval	6.000000e-09
GCST008154_5	Trunk fat mass	3.000000e-07
GCST008865_6	Sphingomyelin 24:0 levels	1.000000e-06
GCST010064_2	Celiac disease	9.000000e-09
GCST010151_10	Carotid intima media thickness x smoking interaction	7.000000e-06
GCST010276_8	Renal underexcretion gout	1.000000e-07
GCST010321_112	PR interval	1.000000e-19
GCST010994_5	High myopia	2.000000e-08
GCST011996_2	dexamethasone sensitivity in B-cell precursor acute lymphoblastic leukaemia	3.000000e-06
GCST011997_2	prednisolone sensitivity in B-cell precursor acute lymphoblastic leukaemia	4.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0007835	alcohol dependence measurement
EFO:0007901	hepcidin:ferritin ratio
EFO:0004462	PR interval
EFO:0010118	sphingomyelin measurement
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	3
methylmercuric chloride	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
trametinib	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Amphotericin B	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	affects methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Melphalan	decreases expression	1
Quercetin	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Tretinoin	increases expression	1

Clinical trials (associated diseases)

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