FRMD8

Summary

FRMD8 (FERM domain containing 8, HGNC:25462) is a protein-coding gene on chromosome 11q13.1, encoding FERM domain-containing protein 8 (Q9BZ67). Promotes the cell surface stability of iRhom1/RHBDF1 and iRhom2/RHBDF2 and prevents their degradation via the endolysosomal pathway.

Involved in positive regulation of tumor necrosis factor production. Located in several cellular components, including centriolar satellite; cytosol; and nucleoplasm.

Source: NCBI Gene 83786 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 167 total
• MANE Select transcript: NM_031904

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25462
Approved symbol	FRMD8
Name	FERM domain containing 8
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ90369, FKSG44, iTAP
Ensembl gene	ENSG00000126391
Ensembl biotype	protein_coding
OMIM	618337
Entrez	83786

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 retained_intron

ENST00000317568, ENST00000355991, ENST00000416776, ENST00000525156, ENST00000526201, ENST00000528854, ENST00000531151, ENST00000531296, ENST00000533782, ENST00000878378, ENST00000878379, ENST00000878380, ENST00000878381, ENST00000954543

RefSeq mRNA: 3 — MANE Select: NM_031904 NM_001300832, NM_001300833, NM_031904

CCDS: CCDS73320, CCDS76432, CCDS8102

Canonical transcript exons

ENST00000317568 — 11 exons

Exon	Start	End
ENSE00000863911	65394041	65394099
ENSE00000863912	65394259	65394425
ENSE00000863914	65399736	65399859
ENSE00000863915	65400724	65400867
ENSE00000863916	65404864	65405068
ENSE00001326375	65393573	65393674
ENSE00002158287	65411242	65413525
ENSE00002198702	65386637	65386761
ENSE00003513786	65389361	65389528
ENSE00003570532	65396799	65397020
ENSE00003647796	65387037	65387121

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.6252 / max 216.8744, expressed in 1808 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115073	18.6252	1808

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.87	gold quality
oviduct epithelium	UBERON:0004804	97.87	gold quality
epithelial cell of pancreas	CL:0000083	96.74	gold quality
amniotic fluid	UBERON:0000173	96.64	gold quality
endothelial cell	CL:0000115	96.52	gold quality
esophagus squamous epithelium	UBERON:0006920	96.23	gold quality
ileal mucosa	UBERON:0000331	94.46	gold quality
lower esophagus mucosa	UBERON:0035834	94.20	gold quality
buccal mucosa cell	CL:0002336	94.05	gold quality
gingival epithelium	UBERON:0001949	93.88	gold quality
tibial nerve	UBERON:0001323	93.64	gold quality
upper leg skin	UBERON:0004262	92.74	gold quality
gingiva	UBERON:0001828	92.04	gold quality
parotid gland	UBERON:0001831	91.62	gold quality
skin of hip	UBERON:0001554	91.57	gold quality
spleen	UBERON:0002106	91.17	gold quality
sural nerve	UBERON:0015488	91.08	gold quality
tibia	UBERON:0000979	91.02	gold quality
esophagus mucosa	UBERON:0002469	90.96	gold quality
granulocyte	CL:0000094	90.70	gold quality
epithelium of nasopharynx	UBERON:0001951	90.61	gold quality
penis	UBERON:0000989	90.43	gold quality
blood	UBERON:0000178	90.28	gold quality
skin of leg	UBERON:0001511	90.00	gold quality
skin of abdomen	UBERON:0001416	89.74	gold quality
palpebral conjunctiva	UBERON:0001812	89.74	gold quality
zone of skin	UBERON:0000014	89.50	gold quality
germinal epithelium of ovary	UBERON:0001304	89.39	gold quality
vagina	UBERON:0000996	89.12	gold quality
sperm	CL:0000019	89.03	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.32
E-GEOD-86618	no	211.13
E-MTAB-7249	no	56.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting FRMD8, 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-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-371B-5P	99.99	75.34	4759
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-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3136-3P	99.57	66.59	781

Literature-anchored findings (GeneRIF, showing 4)

• iTAP (FRMD8) is a novel iRhom2 interactor that controls TNF-alpha secretion by policing the stability of iRhom2/ADAM17 complex. (PMID:29897333)
• FRMD8 promotes inflammatory and growth factor signaling by stabilizing the iRhom2/ADAM17 sheddase complex. (PMID:29897336)
• FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth. (PMID:37527040)
• LINC01002 functions as a ceRNA to regulate FRMD8 by sponging miR-4324 for the development of COVID-19. (PMID:38734674)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	frmd8	ENSDARG00000073696
mus_musculus	Frmd8	ENSMUSG00000024816
rattus_norvegicus	Frmd8	ENSRNOG00000020881
drosophila_melanogaster	Bili	FBGN0039282
caenorhabditis_elegans		WBGENE00001496

Paralogs (1): KRIT1 (ENSG00000001631)

Protein

Protein identifiers

FERM domain-containing protein 8 — Q9BZ67 (reviewed: Q9BZ67)

Alternative names: Band4.1 inhibitor LRP interactor, iRhom tail-associated protein

All UniProt accessions (5): Q9BZ67, E9PRA3, E9PRP1, E9PS62, Q8N4M4

UniProt curated annotations — full annotation on UniProt →

Function. Promotes the cell surface stability of iRhom1/RHBDF1 and iRhom2/RHBDF2 and prevents their degradation via the endolysosomal pathway. By acting on iRhoms, involved in ADAM17-mediated shedding of TNF, amphiregulin/AREG, HBEGF and TGFA from the cell surface. Negatively regulates Wnt signaling, possibly by antagonizing the recruitment of AXIN1 to LRP6.

Subunit / interactions. Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (via cytoplasmic N-termini); this interaction leads to mutual protein stabilization. Interacts with ADAM17; this interaction is indirect and mediated by iRhom proteins. Interacts with LRP6; this interaction affects LRP6-binding to AXIN1.

Subcellular location. Cytoplasm. Cytosol. Cell membrane.

Tissue specificity. Widely expressed, with high expression in heart and spleen.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BZ67-1	1	yes
Q9BZ67-2	2
Q9BZ67-3	3

RefSeq proteins (3): NP_001287761, NP_001287762, NP_114110* (*=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
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR035963	FERM_2	Homologous_superfamily
IPR051594	KRIT1/FRMD8	Family
IPR057096	KRIT1_FRMD8_FERM_C	Domain

Pfam: PF00373, PF24522

UniProt features (15 total): modified residue 8, splice variant 2, region of interest 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZ67-F1	80.63	0.57

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 (8): 439, 446, 1, 24, 383, 387, 408, 419

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 120 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, chr11q13, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_POSITIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_SUPERFAMILY_CYTOKINE_PRODUCTION, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_CYTOKINE_PRODUCTION, GARY_CD5_TARGETS_DN, GOBP_LOCALIZATION_WITHIN_MEMBRANE, RGAGGAARY_PU1_Q6, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GOBP_NEGATIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (3): positive regulation of tumor necrosis factor production (GO:0032760), protein localization to plasma membrane (GO:0072659), negative regulation of canonical Wnt signaling pathway (GO:0090090)

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

GO Cellular Component (7): nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), centriolar satellite (GO:0034451), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
protein localization to membrane	1
protein localization to cell periphery	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
binding	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1
centrosome	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRMD8	RHBDF2	Q6PJF5	821
FRMD8	TIGD3	Q6B0B8	637
FRMD8	SLC25A45	Q8N413	618
FRMD8	TAPBP	O15533	587
FRMD8	RHBDF1	Q96CC6	575
FRMD8	PTCD2	Q8WV60	570
FRMD8	ZNRD2	O60232	549
FRMD8	FAM89B	Q8N5H3	541
FRMD8	EHBP1L1	Q8N3D4	537
FRMD8	C1orf159	Q96HA4	506
FRMD8	DNHD1	Q96M86	473
FRMD8	CCDC60	Q8IWA6	470
FRMD8	ZNHIT2	Q9UHR6	455
FRMD8	CALR	P27797	455
FRMD8	ZNF106	Q9H2Y7	447

IntAct

37 interactions, top by confidence:

A	B	Type	Score
GRAMD2B	FRMD8	psi-mi:“MI:0915”(physical association)	0.720
PLEKHF2	FRMD8	psi-mi:“MI:0915”(physical association)	0.720
FRMD8	GRAMD2B	psi-mi:“MI:0915”(physical association)	0.720
FRMD8	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.720
FRMD8	ZNF446	psi-mi:“MI:0915”(physical association)	0.560
FATE1	FRMD8	psi-mi:“MI:0915”(physical association)	0.560
KCNH2	FRMD8	psi-mi:“MI:0915”(physical association)	0.560
ZNF474	FRMD8	psi-mi:“MI:0915”(physical association)	0.560
FRMD8	LIME1	psi-mi:“MI:0915”(physical association)	0.560
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
RPS14	NVL	psi-mi:“MI:0914”(association)	0.350
ZNF423	SPOP	psi-mi:“MI:0914”(association)	0.350
GLT8D1	SMR3B	psi-mi:“MI:0914”(association)	0.350
HTR1E	ESYT2	psi-mi:“MI:0914”(association)	0.350
SPANXN3	OGA	psi-mi:“MI:0914”(association)	0.350
FRMD8	ZNF446	psi-mi:“MI:0915”(physical association)	0.000
FRMD8	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.000
FRMD8	GRAMD2B	psi-mi:“MI:0915”(physical association)	0.000
FRMD8	FATE1	psi-mi:“MI:0915”(physical association)	0.000
FRMD8	KCNH2	psi-mi:“MI:0915”(physical association)	0.000
FRMD8	ZNF474	psi-mi:“MI:0915”(physical association)	0.000
FRMD8	LIME1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): FRMD8 (Two-hybrid), FRMD8 (Two-hybrid), FRMD8 (Affinity Capture-MS), FRMD8 (Affinity Capture-MS), FRMD8 (Affinity Capture-MS), FRMD8 (Two-hybrid), FRMD8 (Two-hybrid), FATE1 (Two-hybrid), GRAMD3 (Two-hybrid), ZNF474 (Two-hybrid), PLEKHF2 (Two-hybrid), LIME1 (Two-hybrid), FRMD8 (Proximity Label-MS), FRMD8 (Affinity Capture-RNA), FRMD8 (Affinity Capture-MS)

ESM2 similar proteins: A4FV98, A5D7B1, A5PK51, A6QLN9, A8MUP2, D3ZVU9, O15527, O35595, O75078, O95848, P57775, Q05B60, Q06643, Q14728, Q14CX5, Q1LZB9, Q27HK4, Q2T9T5, Q2TBS1, Q3UGX3, Q4R3I0, Q4V892, Q58CT4, Q5E9H2, Q5RCI5, Q5SUV1, Q5TM22, Q642A6, Q6IA17, Q6PCB0, Q6XQN6, Q862Z7, Q8N8L6, Q8R2R5, Q8R2Z5, Q8R366, Q8WUG5, Q95JH0, Q95JH2, Q969P0

Diamond homologs: E7F221, Q0IJ35, Q3UFK8, Q5U2R3, Q7ZWP1, Q9BZ67, Q9BZ68, Q15678, Q62130

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	136
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2456 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65387120:AGGT:A	donor_loss	1.0000
11:65389357:ACAGC:A	acceptor_gain	1.0000
11:65389359:A:AG	acceptor_gain	1.0000
11:65389359:AGC:A	acceptor_gain	1.0000
11:65389360:G:GG	acceptor_gain	1.0000
11:65389360:GCG:G	acceptor_gain	1.0000
11:65389524:GCTGG:G	donor_gain	1.0000
11:65389526:TGGG:T	donor_loss	1.0000
11:65389527:GG:G	donor_gain	1.0000
11:65389527:GGGTA:G	donor_loss	1.0000
11:65389528:GG:G	donor_gain	1.0000
11:65389528:GGTAA:G	donor_loss	1.0000
11:65389529:G:GA	donor_loss	1.0000
11:65389530:T:A	donor_loss	1.0000
11:65394039:A:AG	acceptor_gain	1.0000
11:65394040:G:GG	acceptor_gain	1.0000
11:65394040:GAT:G	acceptor_gain	1.0000
11:65394248:C:G	acceptor_gain	1.0000
11:65394254:TGCA:T	acceptor_loss	1.0000
11:65394257:A:AC	acceptor_loss	1.0000
11:65394257:A:AG	acceptor_gain	1.0000
11:65394258:G:GA	acceptor_gain	1.0000
11:65394258:GAT:G	acceptor_gain	1.0000
11:65394258:GATC:G	acceptor_gain	1.0000
11:65394258:GATCC:G	acceptor_gain	1.0000
11:65394423:GAG:G	donor_gain	1.0000
11:65394424:AGGT:A	donor_loss	1.0000
11:65394426:G:GG	donor_gain	1.0000
11:65396797:A:AG	acceptor_gain	1.0000
11:65396798:G:GG	acceptor_gain	1.0000

AlphaMissense

2988 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65400760:T:A	W322R	1.000
11:65400760:T:C	W322R	1.000
11:65393620:T:A	W101R	0.999
11:65393620:T:C	W101R	0.999
11:65399840:T:A	V303D	0.999
11:65400755:T:C	L320P	0.999
11:65400803:T:C	L336P	0.999
11:65400808:T:C	F338L	0.999
11:65400810:C:A	F338L	0.999
11:65400810:C:G	F338L	0.999
11:65389507:T:A	W78R	0.998
11:65389507:T:C	W78R	0.998
11:65393622:G:C	W101C	0.998
11:65393622:G:T	W101C	0.998
11:65400762:G:C	W322C	0.998
11:65400762:G:T	W322C	0.998
11:65400797:T:C	L334S	0.998
11:65400809:T:C	F338S	0.998
11:65400848:T:C	L351P	0.998
11:65404883:T:C	L364P	0.998
11:65393582:T:C	L88P	0.997
11:65393641:T:C	F108L	0.997
11:65393643:C:A	F108L	0.997
11:65393643:C:G	F108L	0.997
11:65399807:T:A	V292D	0.997
11:65399813:T:A	V294E	0.997
11:65399819:T:A	I296N	0.997
11:65400740:T:C	L315P	0.997
11:65400799:T:A	W335R	0.997
11:65400799:T:C	W335R	0.997

dbSNP variants (sampled 300 via entrez): RS1000078572 (11:65378634 G>T), RS1000173552 (11:65373414 C>A,G), RS1000204767 (11:65373078 C>T), RS1000253045 (11:65413554 T>C), RS1000262445 (11:65402303 G>A,C), RS1000277690 (11:65399242 G>A), RS1000415190 (11:65385799 AAT>A), RS1000438995 (11:65418920 G>A), RS1000452030 (11:65418714 C>T), RS1000511042 (11:65371903 G>A,C), RS1000584157 (11:65374717 C>T), RS1000639810 (11:65409262 T>C), RS1000729800 (11:65413638 T>C,G), RS1000754315 (11:65368607 A>C), RS1000777160 (11:65417773 A>G)

Disease associations

OMIM: gene MIM:618337 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002481_8	Acne (severe)	3.000000e-11
GCST008972_54	Urate levels	7.000000e-90
GCST010002_240	Refractive error	3.000000e-11
GCST010283_1	Serum uric acid levels	1.000000e-28
GCST010512_17	Serum uric acid levels	1.000000e-41
GCST90011898_3	Alanine aminotransferase levels	3.000000e-13
GCST90013405_82	Liver enzyme levels (alanine transaminase)	2.000000e-12
GCST90020026_503	Hip index	2.000000e-09
GCST90020028_1991	Hip circumference adjusted for BMI	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004761	uric acid measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Valproic Acid	increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
beta-lapachone	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, increases expression	1
MT19c compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Aldehydes	increases expression	1
Atrazine	decreases expression	1
Cadmium	increases expression	1
Caffeine	decreases phosphorylation	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1

Clinical trials (associated diseases)

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