EPB41L4A

Summary

EPB41L4A (erythrocyte membrane protein band 4.1 like 4A, HGNC:13278) is a protein-coding gene on chromosome 5q22.1-q22.2, encoding Band 4.1-like protein 4A (Q9HCS5).

The protein encoded by this gene is a member of the band 4.1 protein superfamily. Members of this superfamily are thought to play an important role in regulating interactions between the cytoskeleton and plasma membrane, and contain an amino terminal conserved domain that binds glycophorin C. This gene product is thought to be involved in the beta-catenin signaling pathway.

Source: NCBI Gene 64097 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 180 total — 1 likely-pathogenic
• MANE Select transcript: NM_022140

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13278
Approved symbol	EPB41L4A
Name	erythrocyte membrane protein band 4.1 like 4A
Location	5q22.1-q22.2
Locus type	gene with protein product
Status	Approved
Aliases	NBL4
Ensembl gene	ENSG00000129595
Ensembl biotype	protein_coding
OMIM	612141
Entrez	64097

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding_CDS_not_defined, 4 retained_intron, 1 protein_coding

ENST00000261486, ENST00000305368, ENST00000507810, ENST00000509342, ENST00000511405, ENST00000511790, ENST00000512395, ENST00000513333, ENST00000514203, ENST00000515047

RefSeq mRNA: 3 — MANE Select: NM_022140 NM_001347887, NM_001347888, NM_022140

CCDS: CCDS43350

Canonical transcript exons

ENST00000261486 — 23 exons

Exon	Start	End
ENSE00001535776	112162619	112165118
ENSE00002061902	112418941	112419277
ENSE00003475747	112266233	112266330
ENSE00003479406	112259891	112259979
ENSE00003490951	112209892	112209982
ENSE00003491429	112195661	112195708
ENSE00003502423	112168995	112169105
ENSE00003507362	112204375	112204488
ENSE00003509464	112262494	112262581
ENSE00003537433	112307386	112307490
ENSE00003566638	112264896	112265016
ENSE00003569174	112194568	112194645
ENSE00003579697	112168739	112168820
ENSE00003580972	112239660	112239737
ENSE00003596022	112184016	112184135
ENSE00003597125	112170301	112170369
ENSE00003627378	112259229	112259292
ENSE00003628693	112275326	112275404
ENSE00003633958	112205421	112205504
ENSE00003643274	112170945	112170992
ENSE00003648041	112280272	112280323
ENSE00003667070	112240719	112240810
ENSE00003693576	112234634	112234755

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 94.05.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6947 / max 31.3873, expressed in 674 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62947	0.5709	281
62948	0.5379	301
62950	0.5106	250
62949	0.0600	15
62944	0.0153	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	94.05	gold quality
calcaneal tendon	UBERON:0003701	93.07	gold quality
eye	UBERON:0000970	92.80	gold quality
cortical plate	UBERON:0005343	91.85	gold quality
ventricular zone	UBERON:0003053	91.26	gold quality
esophagus squamous epithelium	UBERON:0006920	91.26	gold quality
sural nerve	UBERON:0015488	90.89	gold quality
lower esophagus mucosa	UBERON:0035834	90.76	gold quality
bronchial epithelial cell	CL:0002328	89.88	gold quality
corpus epididymis	UBERON:0004359	89.48	gold quality
pigmented layer of retina	UBERON:0001782	89.06	gold quality
retina	UBERON:0000966	89.03	gold quality
tendon	UBERON:0000043	87.99	gold quality
epithelium of esophagus	UBERON:0001976	87.96	gold quality
ganglionic eminence	UBERON:0004023	87.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.84	gold quality
gall bladder	UBERON:0002110	86.76	gold quality
vagina	UBERON:0000996	86.72	gold quality
left lobe of thyroid gland	UBERON:0001120	86.64	gold quality
secondary oocyte	CL:0000655	86.58	gold quality
esophagus mucosa	UBERON:0002469	86.56	gold quality
renal medulla	UBERON:0000362	86.39	gold quality
thyroid gland	UBERON:0002046	86.29	gold quality
right lung	UBERON:0002167	86.25	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.11	gold quality
squamous epithelium	UBERON:0006914	86.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.70	gold quality
right uterine tube	UBERON:0001302	85.66	gold quality
right lobe of thyroid gland	UBERON:0001119	84.94	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.53	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	12.99
E-ANND-3	yes	9.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	epb41l4a	ENSDARG00000040087
mus_musculus	Epb41l4a	ENSMUSG00000024376
rattus_norvegicus	Epb41l4a	ENSRNOG00000026050
drosophila_melanogaster	yrt	FBGN0004049
drosophila_melanogaster	Frmd5	FBGN0032225
caenorhabditis_elegans		WBGENE00001489
caenorhabditis_elegans	frm-4	WBGENE00001491

Paralogs (10): MYLIP (ENSG00000007944), EPB41L2 (ENSG00000079819), EPB41L3 (ENSG00000082397), EPB41L1 (ENSG00000088367), EPB41L4B (ENSG00000095203), EPB41L5 (ENSG00000115109), FRMD6 (ENSG00000139926), EPB41 (ENSG00000159023), FRMD5 (ENSG00000171877), FRMD3 (ENSG00000172159)

Protein

Protein identifiers

Band 4.1-like protein 4A — Q9HCS5 (reviewed: Q9HCS5)

Alternative names: Erythrocyte membrane protein band 4.1-like 4A, Protein NBL4

All UniProt accessions (1): Q9HCS5

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in many tissues. High levels of expression in brain, liver, thymus and peripheral blood leukocytes and low levels of expression in heart, kidney, testis and colon.

RefSeq proteins (2): NP_001334816, NP_071423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR000798	Ez/rad/moesin-like	Family
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR014847	FA	Domain
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR030696	Band4.1-like4A_FERM_F1	Domain
IPR035963	FERM_2	Homologous_superfamily

Pfam: PF00373, PF08736, PF09379, PF09380

UniProt features (22 total): compositionally biased region 8, sequence conflict 6, modified residue 4, chain 1, domain 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCS5-F1	66.14	0.37

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 (4): 304, 389, 393, 402

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, BENPORATH_ES_WITH_H3K27ME3, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, DOANE_RESPONSE_TO_ANDROGEN_DN, BILD_E2F3_ONCOGENIC_SIGNATURE, GOBP_ACTOMYOSIN_STRUCTURE_ORGANIZATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, MODULE_48, MODULE_207, MODULE_95, CUI_TCF21_TARGETS_2_UP

GO Biological Process (1): actomyosin structure organization (GO:0031032)

GO Molecular Function (1): cytoskeletal protein binding (GO:0008092)

GO Cellular Component (3): cytoskeleton (GO:0005856), membrane (GO:0016020), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
actin cytoskeleton organization	1
protein binding	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

726 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPB41L4A	TAAR1	Q96RJ0	813
EPB41L4A	PCNX2	A6NKB5	493
EPB41L4A	DYNLL2	Q96FJ2	465
EPB41L4A	KIAA1755	Q5JYT7	459
EPB41L4A	ALAD	P13716	438
EPB41L4A	SLC6A7	Q99884	414
EPB41L4A	CTNNB1	P35222	409
EPB41L4A	ARHGEF37	A1IGU5	399
EPB41L4A	ZNF658	Q5TYW1	395
EPB41L4A	TCEA2	Q15560	391
EPB41L4A	ITM2C	Q9NQX7	388
EPB41L4A	EML6	Q6ZMW3	386
EPB41L4A	AR	P10275	381
EPB41L4A	TLCD3B	Q71RH2	381
EPB41L4A	BAIAP2	Q9UQB8	379

IntAct

8 interactions, top by confidence:

A	B	Type	Score
DVL3	DVL2	psi-mi:“MI:0914”(association)	0.530
SRPK2	EPB41L4A	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EPB41L4A	SRPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EPB41L4A	TNS2	psi-mi:“MI:0915”(physical association)	0.370
EPB41L4A	FGFR1	psi-mi:“MI:0914”(association)	0.350
EPB41L4A	NME2P1	psi-mi:“MI:0914”(association)	0.350
	EBAG9	psi-mi:“MI:0914”(association)	0.350

BioGRID (131): EPB41L4A (Two-hybrid), EPB41L4A (Affinity Capture-RNA), EPB41L4A (Two-hybrid), EPB41L4A (Synthetic Lethality), EPB41L4A (Affinity Capture-RNA), EPB41L4A (Proximity Label-MS), ANK3 (Proximity Label-MS), ANKRD26 (Proximity Label-MS), APC (Proximity Label-MS), ATP2B1 (Proximity Label-MS), BASP1 (Proximity Label-MS), CASK (Proximity Label-MS), CCDC88A (Proximity Label-MS), CDC42BPA (Proximity Label-MS), CEP89 (Proximity Label-MS)

ESM2 similar proteins: A0A0R4IXF6, A1A5R8, A9ZLX4, D3YXJ0, E9PUQ8, G3UZ78, O00750, O15164, O54828, P30052, P40818, P48984, P52963, P59997, P97496, Q02225, Q08AX9, Q08BR4, Q08D35, Q16760, Q1LUC3, Q2I6J1, Q3UWM4, Q498F0, Q5JSH3, Q5JTW2, Q5RHD1, Q60665, Q64398, Q68FF0, Q6INA9, Q6NSI8, Q6NVE8, Q6PDG5, Q6ZMT4, Q7ZVP1, Q80U87, Q86XP1, Q8C5W4, Q8N7X0

Diamond homologs: A2A2Y4, A2AD83, A2ALK8, B2RYE5, F1LYQ8, F1P065, F8VPU2, O43491, O57457, O70318, O94887, P11171, P11434, P26045, P28191, P29074, P48193, P52963, Q0P4Q4, Q54K81, Q58CU2, Q5FVG2, Q5R803, Q5RAB8, Q6P5H6, Q6Q7P4, Q6ZUT3, Q7Z6J6, Q8BGS1, Q8BHD4, Q91VS8, Q9H329, Q9H4G0, Q9HCM4, Q9HCS5, Q9JMC8, Q9MYU8, Q9N179, Q9V8R9, Q9WTP0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	125
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
183292	NM_022140.5(EPB41L4A):c.1298C>T (p.Ser433Leu)	Likely pathogenic

SpliceAI

5956 predictions. Top by Δscore:

Variant	Effect	Δscore
5:112168734:CTAA:C	donor_loss	1.0000
5:112168736:AAC:A	donor_loss	1.0000
5:112168737:A:AT	donor_loss	1.0000
5:112168738:CC:C	donor_loss	1.0000
5:112168816:TTGAA:T	acceptor_gain	1.0000
5:112168821:C:CC	acceptor_gain	1.0000
5:112168993:A:AC	donor_gain	1.0000
5:112168994:C:CC	donor_gain	1.0000
5:112168994:CTT:C	donor_gain	1.0000
5:112168994:CTTCA:C	donor_gain	1.0000
5:112169001:T:TA	donor_gain	1.0000
5:112169119:C:CT	acceptor_gain	1.0000
5:112169120:A:T	acceptor_gain	1.0000
5:112169127:A:C	acceptor_gain	1.0000
5:112170299:A:AC	donor_gain	1.0000
5:112170300:C:CC	donor_gain	1.0000
5:112170300:CT:C	donor_gain	1.0000
5:112170300:CTCT:C	donor_gain	1.0000
5:112170300:CTCTA:C	donor_gain	1.0000
5:112170365:CTTTT:C	acceptor_gain	1.0000
5:112170366:TTTTC:T	acceptor_loss	1.0000
5:112170368:TT:T	acceptor_gain	1.0000
5:112170370:C:CA	acceptor_loss	1.0000
5:112170370:C:CC	acceptor_gain	1.0000
5:112170371:T:A	acceptor_loss	1.0000
5:112170382:A:C	acceptor_gain	1.0000
5:112170940:CTCA:C	donor_gain	1.0000
5:112170943:A:AC	donor_gain	1.0000
5:112170944:C:CC	donor_gain	1.0000
5:112170944:CTG:C	donor_gain	1.0000

AlphaMissense

4509 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:112259248:A:G	L259P	0.999
5:112259892:A:G	W244R	0.999
5:112259892:A:T	W244R	0.999
5:112259936:C:T	G229D	0.999
5:112262516:C:T	G207D	0.999
5:112259292:C:A	W244C	0.998
5:112259292:C:G	W244C	0.998
5:112259898:A:C	Y242D	0.998
5:112259933:A:T	V230D	0.998
5:112259937:C:G	G229R	0.998
5:112259951:C:T	G224E	0.998
5:112259952:C:G	G224R	0.998
5:112259952:C:T	G224R	0.998
5:112262516:C:A	G207V	0.998
5:112266286:C:G	R127P	0.998
5:112280316:A:G	L71P	0.998
5:112280320:A:G	W70R	0.998
5:112280320:A:T	W70R	0.998
5:112307468:A:T	V41D	0.998
5:112418996:A:T	V15D	0.998
5:112240763:G:C	C281W	0.997
5:112259254:A:G	F257S	0.997
5:112259897:T:G	Y242S	0.997
5:112259898:A:G	Y242H	0.997
5:112259927:A:T	V232E	0.997
5:112262498:A:T	V213D	0.997
5:112262513:A:T	V208D	0.997
5:112262517:C:G	G207R	0.997
5:112266283:A:G	L128P	0.997
5:112307411:C:G	R60P	0.997

dbSNP variants (sampled 300 via entrez): RS1000008681 (5:112202786 G>C), RS1000017565 (5:112224423 G>C), RS1000020307 (5:112367274 A>G), RS1000026637 (5:112274139 G>A,C), RS1000053738 (5:112297695 G>A), RS1000054798 (5:112346987 G>A), RS1000061019 (5:112203002 A>G), RS1000071314 (5:112297346 G>C), RS1000079704 (5:112390804 C>A,G,T), RS1000083716 (5:112316814 C>A,T), RS1000093771 (5:112165239 A>C,G,T), RS1000095283 (5:112275121 G>A,C), RS1000100631 (5:112165686 C>T), RS1000133132 (5:112387515 G>A,C), RS1000147492 (5:112223576 G>A,C)

Disease associations

OMIM: gene MIM:612141 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001188_8	vWF and FVIII levels	1.000000e-06
GCST002974_3	Suicide ideation score in major depressive disorder	5.000000e-06
GCST003542_54	Night sleep phenotypes	4.000000e-06
GCST003542_55	Night sleep phenotypes	5.000000e-06
GCST004144_8	Thyroid cancer	3.000000e-10
GCST005182_3	Common carotid intima-media thickness in HIV negative individuals	2.000000e-06
GCST010002_35	Refractive error	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007619	suicide ideation 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
Valproic Acid	affects expression, decreases methylation, increases expression	6
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
bisphenol A	affects expression, decreases expression	2
Air Pollutants	increases abundance, decreases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Silicon Dioxide	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
ferrous chloride	decreases expression	1
cupric chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
incobotulinumtoxinA	increases expression	1
Sunitinib	increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Bucladesine	affects cotreatment, increases expression	1
Estrogens	decreases expression, decreases reaction	1
Progesterone	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1

Clinical trials (associated diseases)

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