FRMD4A

Summary

FRMD4A (FERM domain containing 4A, HGNC:25491) is a protein-coding gene on chromosome 10p13, encoding FERM domain-containing protein 4A (Q9P2Q2). Scaffolding protein that regulates epithelial cell polarity by connecting ARF6 activation with the PAR3 complex.

This gene encodes a FERM domain-containing protein that regulates epithelial cell polarity. It connects ADP ribosylation factor 6 (ARF6) with the Par protein complex, which regulates the remodeling of adherens junctions and linear actin cable formation during epithelial cell polarization. Polymorphisms in this gene are associated with Alzheimer’s disease, and also with nicotine dependence. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55691 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome (Strong, GenCC)
• GWAS associations: 23
• Clinical variants (ClinVar): 265 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_018027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25491
Approved symbol	FRMD4A
Name	FERM domain containing 4A
Location	10p13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10210, KIAA1294, bA295P9.4
Ensembl gene	ENSG00000151474
Ensembl biotype	protein_coding
OMIM	616305
Entrez	55691

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 16 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000264546, ENST00000342409, ENST00000357447, ENST00000475141, ENST00000475325, ENST00000477221, ENST00000492155, ENST00000493380, ENST00000495956, ENST00000632314, ENST00000632570, ENST00000640906, ENST00000648400, ENST00000648761, ENST00000649099, ENST00000649155, ENST00000649246, ENST00000649423, ENST00000649947, ENST00000650014, ENST00000650137

RefSeq mRNA: 3 — MANE Select: NM_018027 NM_001318336, NM_001318337, NM_018027

CCDS: CCDS7101

Canonical transcript exons

ENST00000357447 — 25 exons

Exon	Start	End
ENSE00000999813	13762624	13762680
ENSE00001094865	13761647	13761669
ENSE00001094870	13737844	13737930
ENSE00001094873	13858847	13858912
ENSE00001094879	13670406	13670528
ENSE00001155710	13740194	13740251
ENSE00001155717	13740512	13740577
ENSE00001155723	13747736	13747819
ENSE00001274244	13693898	13694039
ENSE00001314803	13674911	13675044
ENSE00001477839	14330597	14330924
ENSE00001526579	13643706	13647035
ENSE00001614936	13656636	13657522
ENSE00001733230	13660316	13660553
ENSE00001738789	13659323	13659490
ENSE00001765025	13663453	13663509
ENSE00001789941	13651903	13651974
ENSE00002309383	13666097	13666325
ENSE00003514477	13701340	13701478
ENSE00003524307	13810814	13810908
ENSE00003562195	13796496	13796588
ENSE00003598038	14330058	14330183
ENSE00003602401	13782922	13783006
ENSE00003621096	13707037	13707113
ENSE00003647110	13654416	13654512

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 97.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.7890 / max 418.5664, expressed in 1622 samples.

FANTOM5 promoters (38 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108313	9.3897	1305
108333	3.7446	1035
108350	1.9059	633
108349	1.4560	539
108348	1.1884	511
108366	1.0757	134
108346	0.9644	457
108311	0.7810	325
108351	0.7584	200
108339	0.4647	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.32	gold quality
ganglionic eminence	UBERON:0004023	94.34	gold quality
oocyte	CL:0000023	94.21	gold quality
adipose tissue	UBERON:0001013	93.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.80	gold quality
cortical plate	UBERON:0005343	93.55	gold quality
connective tissue	UBERON:0002384	93.52	gold quality
left coronary artery	UBERON:0001626	93.33	gold quality
coronary artery	UBERON:0001621	93.21	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.07	gold quality
popliteal artery	UBERON:0002250	93.03	gold quality
tibial artery	UBERON:0007610	93.03	gold quality
corpus callosum	UBERON:0002336	93.01	gold quality
omental fat pad	UBERON:0010414	92.93	gold quality
peritoneum	UBERON:0002358	92.90	gold quality
spleen	UBERON:0002106	92.62	gold quality
nerve	UBERON:0001021	92.51	gold quality
tibial nerve	UBERON:0001323	92.51	gold quality
right lung	UBERON:0002167	92.46	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.30	gold quality
nipple	UBERON:0002030	92.26	gold quality
right coronary artery	UBERON:0001625	92.23	gold quality
parietal pleura	UBERON:0002400	92.15	gold quality
ventricular zone	UBERON:0003053	92.00	gold quality
secondary oocyte	CL:0000655	91.82	gold quality
aorta	UBERON:0000947	91.33	gold quality
skin of abdomen	UBERON:0001416	90.89	gold quality
visceral pleura	UBERON:0002401	90.84	gold quality
renal medulla	UBERON:0000362	90.83	gold quality
metanephros cortex	UBERON:0010533	90.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	12620.83
E-GEOD-180759	yes	5089.84
E-HCAD-30	yes	4685.92
E-MTAB-11268	yes	2581.39
E-GEOD-131882	yes	2344.80
E-CURD-119	yes	2187.73
E-HCAD-25	yes	37.09
E-ANND-3	yes	8.00
E-MTAB-10042	no	64.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting FRMD4A, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-372-3P	99.83	70.58	1691

Literature-anchored findings (GeneRIF, showing 7)

• A single nucleotide polymorphism in the FERM domain containing 4A protein is associated with nicotine dependence. (PMID:22006218)
• data suggest that FRMD4A could be a relevant candidate gene for AD risk. (PMID:22430674)
• findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified (PMID:22564525)
• novel microcephaly, intellectual disability and dysmorphism syndrome is associated with a mutation in FRMD4A. (PMID:25388005)
• FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer’s disease, regulates tau secretion by activating cytohesin-Arf6 signaling. (PMID:27044754)
• Findings suggest that FRMD4A expression correlates with the development of tongue squamous cell carcinoma. (PMID:27666346)
• Polymorphisms in the FRMD4A Gene Are Associated With Chronic Obstructive Pulmonary Disease Susceptibility in a Latin American Population.", trans “Polimorfismos en el gen FRMD4A se asocian a riesgo de enfermedad pulmonar obstructiva cronica en poblacion latinoamericana. (PMID:35312514)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	frmd4a	ENSDARG00000042249
mus_musculus	Frmd4a	ENSMUSG00000026657
rattus_norvegicus	Frmd4a	ENSRNOG00000018500
caenorhabditis_elegans		WBGENE00008555

Paralogs (6): EZR (ENSG00000092820), FRMD4B (ENSG00000114541), ERMN (ENSG00000136541), RDX (ENSG00000137710), MSN (ENSG00000147065), NF2 (ENSG00000186575)

Protein

Protein identifiers

FERM domain-containing protein 4A — Q9P2Q2 (reviewed: Q9P2Q2)

All UniProt accessions (14): A0A0J9YWI3, A0A0J9YXB2, A0A0J9YYA7, A0A1W2PQE7, A0A3B3IRJ0, A0A3B3IS86, A0A3B3ISB3, A0A3B3ISM0, A0A3B3ISM9, A0A3B3ISR1, Q9P2Q2, Q5T376, S4R324, S4R3Y6

UniProt curated annotations — full annotation on UniProt →

Function. Scaffolding protein that regulates epithelial cell polarity by connecting ARF6 activation with the PAR3 complex. Plays a redundant role with FRMD4B in epithelial polarization. May regulate MAPT secretion by activating ARF6-signaling.

Subunit / interactions. Interacts (via coiled-coil domain) with CYTH1 (via coiled-coil domain). Interacts with PARD3 (via coiled-coil domain). Found in a complex with PARD3, CYTH1 and FRMD4A. Interacts with CYTH2. Interacts with CYTH3.

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

Disease relevance. Agenesis of the corpus callosum, with facial anomalies and cerebellar ataxia (CCAFCA) [MIM:616819] An autosomal recessive intellectual disability syndrome characterized by congenital microcephaly, low anterior hairline, bitemporal narrowing, low-set protruding ears, strabismus and tented thick eyebrows with sparse hair in their medial segment. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (3): NP_001305265, NP_001305266, NP_060497* (*=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 (30 total): compositionally biased region 9, region of interest 8, modified residue 8, chain 1, domain 1, coiled-coil region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2Q2-F1	62.95	0.32

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): 530, 604, 615, 681, 711, 800, 872, 901

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 333 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_ESTABLISHMENT_OF_EPITHELIAL_CELL_POLARITY, GCANCTGNY_MYOD_Q6, SP3_Q3, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, FOXO4_01, CACCAGC_MIR138, GGGTGGRR_PAX4_03, HATADA_METHYLATED_IN_LUNG_CANCER_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, FOXD3_01, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, GOBP_REGULATION_OF_PROTEIN_SECRETION

GO Biological Process (3): negative regulation of protein secretion (GO:0050709), positive regulation of protein secretion (GO:0050714), establishment of epithelial cell polarity (GO:0090162)

GO Molecular Function (1): protein-macromolecule adaptor activity (GO:0030674)

GO Cellular Component (5): 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
protein secretion	2
regulation of protein secretion	2
negative regulation of protein transport	1
negative regulation of secretion by cell	1
positive regulation of protein transport	1
positive regulation of secretion by cell	1
establishment of cell polarity	1
protein binding	1
molecular adaptor activity	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

796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRMD4A	CYTH1	Q15438	840
FRMD4A	CYTH2	Q99418	657
FRMD4A	CYTH3	O43739	652
FRMD4A	CYTH4	Q9UIA0	649
FRMD4A	RUFY2	Q8WXA3	583
FRMD4A	MYO1G	B0I1T2	511
FRMD4A	REEP3	Q6NUK4	498
FRMD4A	MYO5C	Q9NQX4	477
FRMD4A	C11orf52	Q96A22	471
FRMD4A	PICALM	Q13492	471
FRMD4A	SLCO3A1	Q9UIG8	463
FRMD4A	NEK7	Q8TDX7	450
FRMD4A	STK35	Q8TDR2	423
FRMD4A	ARL4C	P56559	419
FRMD4A	ATP9A	O75110	416

IntAct

30 interactions, top by confidence:

A	B	Type	Score
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
PPP2R3A	WTIP	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
WDR83	SH2B2	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
FRMD4A	HIST2H2BF	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
WDR83	PIKFYVE	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
CDH12	ARVCF	psi-mi:“MI:0914”(association)	0.350
CYTH1	BACH1	psi-mi:“MI:0914”(association)	0.350
CYTH4	OFD1	psi-mi:“MI:0914”(association)	0.350
CYTH1	CYTH3	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FAM170A	MCM3AP	psi-mi:“MI:0914”(association)	0.350
FTL		psi-mi:“MI:0914”(association)	0.350
WDR83	ISY1-RAB43	psi-mi:“MI:0914”(association)	0.350
SLC9A2	MEIOC	psi-mi:“MI:0914”(association)	0.350
FRMD4A	TRAF3IP1	psi-mi:“MI:0915”(physical association)	0.000
TRAF3IP1	FRMD4A	psi-mi:“MI:0915”(physical association)	0.000
FRMD4A	metG1	psi-mi:“MI:0915”(physical association)	0.000
cutC	FRMD4A	psi-mi:“MI:0915”(physical association)	0.000
FRMD4A	prfB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Proximity Label-MS), FRMD4A (Proximity Label-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), FRMD4A (Affinity Capture-MS), RPL6 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A1L1C7, O08873, O42611, O60716, O94776, O94967, P83094, Q01826, Q0P5J8, Q15542, Q3UHE1, Q3UVG3, Q4R8N2, Q58A45, Q5EY87, Q5JSJ4, Q5M7R9, Q5R7S4, Q5RAR8, Q5TKA1, Q60611, Q640Q5, Q658Y4, Q68FH0, Q6ISB3, Q6NT76, Q6TEP1, Q80U28, Q8BIE6, Q8BJA3, Q8C092, Q8C0V0, Q8C735, Q8C8N2, Q8CGF6, Q8K5C0, Q8N9R8, Q8VI24, Q8WXG6, Q90ZY6

Diamond homologs: 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, Q2HJ49, Q32LP2, Q54EW0, Q5RAB8, Q63648, Q64512

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	181
Likely benign	35
Benign	16

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
222035	NM_018027.5(FRMD4A):c.2134_2146dup (p.Gly716fs)	Pathogenic
3065717	NM_018027.5(FRMD4A):c.110A>G (p.Gln37Arg)	Likely pathogenic
3220924	NM_018027.5(FRMD4A):c.3078delinsCATTCT (p.Asp1027fs)	Likely pathogenic

SpliceAI

7751 predictions. Top by Δscore:

Variant	Effect	Δscore
10:13654526:G:C	acceptor_gain	1.0000
10:13654526:G:GC	acceptor_gain	1.0000
10:13654530:A:T	acceptor_gain	1.0000
10:13659318:CTCA:C	donor_loss	1.0000
10:13659319:TCA:T	donor_loss	1.0000
10:13659320:CA:C	donor_loss	1.0000
10:13659321:ACC:A	donor_loss	1.0000
10:13659322:C:CT	donor_loss	1.0000
10:13659322:CCT:C	donor_gain	1.0000
10:13659488:CTG:C	acceptor_gain	1.0000
10:13659489:TG:T	acceptor_gain	1.0000
10:13659491:C:CC	acceptor_gain	1.0000
10:13660551:CTT:C	acceptor_gain	1.0000
10:13660554:C:CC	acceptor_gain	1.0000
10:13666096:CCGT:C	donor_gain	1.0000
10:13666133:T:TA	donor_gain	1.0000
10:13666322:CTTC:C	acceptor_gain	1.0000
10:13666323:TTC:T	acceptor_gain	1.0000
10:13666324:TC:T	acceptor_gain	1.0000
10:13666324:TCCT:T	acceptor_loss	1.0000
10:13666325:CC:C	acceptor_gain	1.0000
10:13666326:C:CC	acceptor_gain	1.0000
10:13666326:CT:C	acceptor_loss	1.0000
10:13670409:T:A	donor_gain	1.0000
10:13670537:G:C	acceptor_gain	1.0000
10:13674909:A:AC	donor_gain	1.0000
10:13674910:C:CC	donor_gain	1.0000
10:13674910:CAG:C	donor_gain	1.0000
10:13693892:GCCTA:G	donor_loss	1.0000
10:13693893:CCTA:C	donor_loss	1.0000

AlphaMissense

6786 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:13657001:A:T	V863D	1.000
10:13657008:A:C	Y861D	1.000
10:13657013:C:T	G859D	1.000
10:13657014:C:G	G859R	1.000
10:13666147:C:G	R518P	1.000
10:13666180:A:G	L507P	1.000
10:13666193:C:G	A503P	1.000
10:13666212:C:A	R496S	1.000
10:13666212:C:G	R496S	1.000
10:13666213:C:A	R496M	1.000
10:13666213:C:G	R496T	1.000
10:13666255:A:G	L482P	1.000
10:13666255:A:T	L482Q	1.000
10:13666264:G:T	A479D	1.000
10:13666265:C:G	A479P	1.000
10:13666267:G:T	A478D	1.000
10:13666268:C:G	A478P	1.000
10:13666276:A:C	I475S	1.000
10:13666276:A:G	I475T	1.000
10:13666276:A:T	I475N	1.000
10:13666283:A:G	S473P	1.000
10:13670442:G:C	F446L	1.000
10:13670442:G:T	F446L	1.000
10:13670444:A:G	F446L	1.000
10:13674913:C:G	A417P	1.000
10:13674936:A:G	L409P	1.000
10:13674957:A:G	L402P	1.000
10:13674969:A:G	L398P	1.000
10:13693911:G:C	S368R	1.000
10:13693911:G:T	S368R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002108 (10:14034533 C>T), RS1000015567 (10:13725605 T>C), RS1000016771 (10:14202560 C>T), RS1000020842 (10:13932169 C>A), RS1000023690 (10:13864293 G>A,T), RS1000024752 (10:14169565 C>CA), RS1000025971 (10:13815412 G>T), RS1000028065 (10:13829548 C>G,T), RS1000028907 (10:13967292 G>A,T), RS1000030025 (10:13849378 C>A,T), RS1000030636 (10:13964428 C>G,T), RS1000033192 (10:13896241 T>G), RS1000034949 (10:13755408 T>C), RS1000041458 (10:14164276 C>CCG), RS1000041669 (10:13880678 T>C)

Disease associations

OMIM: gene MIM:616305 | disease phenotypes: MIM:616819

GenCC curated gene-disease

Disease	Classification	Inheritance
severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome	Strong	Autosomal recessive

Mondo (2): severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome (MONDO:0014787), microcephaly (MONDO:0001149)

Orphanet (1): Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome (Orphanet:466688)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000179	Thick lower lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000294	Low anterior hairline
HP:0000341	Narrow forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001338	Partial agenesis of the corpus callosum
HP:0001344	Absent speech
HP:0001510	Growth delay
HP:0002465	Poor speech
HP:0002470	Nonprogressive cerebellar ataxia
HP:0002509	Limb hypertonia
HP:0002553	Highly arched eyebrow
HP:0007370	Aplasia/Hypoplasia of the corpus callosum
HP:0008070	Sparse hair

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000451_20	RR interval (heart rate)	1.000000e-06
GCST001449_1	Alzheimer’s disease	1.000000e-10
GCST003096_5	Adiponectin levels	6.000000e-06
GCST003820_4	Knee osteoarthritis	6.000000e-06
GCST004227_7	Obstetric antiphospholipid syndrome	6.000000e-07
GCST004412_9	Craniofacial microsomia	2.000000e-07
GCST004621_10	Red cell distribution width	1.000000e-16
GCST005441_7	Alcohol consumption (max-drinks)	3.000000e-06
GCST006575_19	Takayasu arteritis	3.000000e-07
GCST006804_131	Red cell distribution width	9.000000e-10
GCST007469_7	Rapid automatized naming of digits	1.000000e-06
GCST008876_36	Non-lobar intracerebral hemorrhage (MTAG)	6.000000e-06
GCST010249_2	Chronic obstructive pulmonary disease	3.000000e-06
GCST010818_2	Gut microbiota alpha diversity (PD_whole_tree index)	5.000000e-06
GCST010818_24	Gut microbiota alpha diversity (PD_whole_tree index)	9.000000e-06
GCST011351_14	Aspartate aminotransferase levels	4.000000e-08
GCST011494_52	Daytime nap	4.000000e-23
GCST012322_38	Triglyceride levels x SSRI defined daily dose interaction in schizophrenia or bipolar disorder	1.000000e-07
GCST90002383_480	Hematocrit	3.000000e-15
GCST90002384_183	Hemoglobin	1.000000e-15
GCST90002403_255	Red blood cell count	3.000000e-12
GCST90002404_482	Red cell distribution width	4.000000e-36
GCST90013410_24	Basal cell carcinoma	4.000000e-10

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004831	RR interval
EFO:0004502	adiponectin measurement
EFO:0009188	Red cell distribution width
EFO:0005301	reading and spelling ability
EFO:0010178	non-lobar intracerebral hemorrhage
EFO:0007874	gut microbiome measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0007828	daytime rest measurement
EFO:0004530	triglyceride measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	4
bisphenol A	affects methylation, affects cotreatment, increases methylation, decreases expression	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Dexamethasone	decreases expression, affects cotreatment	2
Doxorubicin	decreases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Particulate Matter	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
trichostatin A	decreases expression, increases expression	1
2-butenal	decreases expression	1
sodium arsenite	affects methylation	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B5ND	PGPC14_26	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.