HEPACAM

Summary

HEPACAM (hepatic and glial cell adhesion molecule, HGNC:26361) is a protein-coding gene on chromosome 11q24.2, encoding Hepatic and glial cell adhesion molecule (Q14CZ8). Involved in regulating cell motility and cell-matrix interactions.

The protein encoded by this gene is a single-pass type I membrane protein that localizes to the cytoplasmic side of the cell membrane. The encoded protein acts as a homodimer and is involved in cell motility and cell-matrix interactions. The expression of this gene is downregulated or undetectable in many cancer cell lines, so this may be a tumor suppressor gene.

Source: NCBI Gene 220296 — RefSeq curated summary.

At a glance

• Gene–disease (curated): megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 324 total — 11 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 60
• MANE Select transcript: NM_152722

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26361
Approved symbol	HEPACAM
Name	hepatic and glial cell adhesion molecule
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25530, GLIALCAM
Ensembl gene	ENSG00000165478
Ensembl biotype	protein_coding
OMIM	611642
Entrez	220296

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000298251, ENST00000526273, ENST00000528971, ENST00000703807, ENST00000872127, ENST00000872128, ENST00000872129

RefSeq mRNA: 2 — MANE Select: NM_152722 NM_001411043, NM_152722

CCDS: CCDS8456, CCDS91616

Canonical transcript exons

ENST00000298251 — 7 exons

Exon	Start	End
ENSE00001093431	124922388	124922458
ENSE00001093440	124923340	124923433
ENSE00001093442	124923729	124924010
ENSE00001160974	124924728	124925069
ENSE00001230650	124919205	124921440
ENSE00003989963	124935922	124936047
ENSE00003989964	124922745	124922818

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 98.16.

FANTOM5 (CAGE): breadth broad, TPM avg 18.3638 / max 4406.5596, expressed in 207 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122974	8.6422	169
122971	6.7721	145
122977	1.7493	116
122973	0.5875	83
122975	0.2284	85
122978	0.1102	56
122972	0.0932	43
122976	0.0814	52
122979	0.0586	40
122970	0.0410	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	98.16	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.42	gold quality
medial globus pallidus	UBERON:0002477	96.91	gold quality
entorhinal cortex	UBERON:0002728	96.65	gold quality
globus pallidus	UBERON:0001875	96.52	gold quality
caudate nucleus	UBERON:0001873	95.94	gold quality
substantia nigra pars compacta	UBERON:0001965	95.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.59	gold quality
postcentral gyrus	UBERON:0002581	95.28	gold quality
amygdala	UBERON:0001876	95.14	gold quality
primary visual cortex	UBERON:0002436	95.13	gold quality
temporal lobe	UBERON:0001871	95.11	gold quality
putamen	UBERON:0001874	94.73	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.65	gold quality
superior frontal gyrus	UBERON:0002661	94.55	gold quality
nucleus accumbens	UBERON:0001882	94.54	gold quality
substantia nigra	UBERON:0002038	94.32	gold quality
spinal cord	UBERON:0002240	94.03	gold quality
Ammon’s horn	UBERON:0001954	94.00	gold quality
corpus callosum	UBERON:0002336	93.97	gold quality
midbrain	UBERON:0001891	93.81	gold quality
parietal lobe	UBERON:0001872	93.65	gold quality
right frontal lobe	UBERON:0002810	93.41	gold quality
middle temporal gyrus	UBERON:0002771	93.16	gold quality
occipital lobe	UBERON:0002021	93.15	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.84	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.31	gold quality
frontal cortex	UBERON:0001870	92.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.95	gold quality
anterior cingulate cortex	UBERON:0009835	91.90	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-76312	yes	26.03
E-GEOD-81608	yes	12.88
E-GEOD-84465	yes	11.00
E-CURD-6	yes	8.42
E-ANND-3	no	0.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting HEPACAM, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309

Literature-anchored findings (GeneRIF, showing 40)

• encodes an Ig-like transmembrane glycoprotein and is involved in cell adhesion and growth control (PMID:15885354)
• the cytoplasmic domain of hepaCAM is essential to its function on cell-matrix interaction and cell motility (PMID:15917256)
• study examined the glycosylation of the GlialCAM (hepaCAM) extracellular domain expressed in HEK and CHO cells (PMID:18082421)
• GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system. (PMID:18293412)
• the expression of hepaCAM in MCF7 cells not only inhibits cell growth but also induces cellular senescence through the p53/21 pathway (PMID:18845560)
• hepaCAM is partially localized in the lipid rafts/caveolae and interacts with Cav-1 through its first immunoglobulin domain. (PMID:19059381)
• The data suggest that an intact hepaCAM protein is critical for establishing a stable physical association with the actin cytoskeleton; and such association is important for modulating hepaCAM-mediated cell adhesion and motility. (PMID:19142852)
• high expression of hepaCAM significantly accelerated cell adhesion but inhibited cell proliferation and migration; cell differentiation was noticeably less apparent in cells expressing low-level hepaCAM (PMID:19507233)
• HepaCAM is involved in cell adhesion and growth control, and its expression is frequently silenced in TCCB. The extracellular domain of hepaCAM is essential to its physiological and biological functions. (PMID:20205955)
• The truncation mutant of hepaCAM failed to promote cell-ECM adhesion and migration, and lost the inhibitory effects on cell growth, suggesting a regulatory role of the cleavage in hepaCAM functions. (PMID:20514407)
• There is a close relationship between hepaCAM and VEGF in urothelial carcinoma (PMID:20593288)
• Downregulation of hepaCAM expression plays an important role in the tumorigenesis and development of bladder cancer (PMID:20628239)
• Dominant HEPACAM mutations can cause either macrocephaly and mental retardation with or without autism or benign familial macrocephaly. (PMID:21419380)
• Research implies that the decrease in c-Myc protein expression, resulting from ectopic expression of hepaCAM, may contribute to the inhibition of proliferation in these cells. (PMID:21618595)
• study presents more detailed characterization of the effect of mutations found in MLC1 and GLIALCAM megalencephalic leukoencephalopathy with subcortical cysts (PMID:21624973)
• Results suggest an important connection between HEPACAM and interferon-gamma, which may inhibit BIU-87 proliferation through HEPACAM re-expression and p21(WAF1) up-regulation to arrest cells at the G(0)/G(1) phase (PMID:22906662)
• results indicate GlialCAM is necessary for MLC1 protein expression, and its reduction affects the activity of volume-regulated anion currents (VRAC) which may cause astrocyte vacuolation; work extends the role of GlialCAM as a chaperone of MLC1 needed for proper VRAC activation (PMID:23793458)
• analysis of mutations in GLIALCAM in patients with megalencephalic leukoencephalopathy with subcortical cysts [case report] (PMID:24202401)
• Re-activation of hepaCAM gene by 5-aza-CdR can inhibit growth of cancer cells and arrest cells at G0/G1 phase (PMID:24324362)
• HepaCAM may prevent the translocation of PKCepsilon from cytosolic to particulate fractions, resulting in the inhibition of 786-0 cell proliferation. (PMID:24515280)
• No clear association between GLIALCAM mutations and an autism-epilepsy phenotype. (PMID:24580998)
• High expression of hepaCAM is associated with renal carcinoma. (PMID:24645843)
• results suggested that HepaCAM acted as a tumor suppressor in prostate cancer (PMID:24811146)
• we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype. (PMID:24824219)
• Results allow classifying the effect of HEPACAM gene mutations in different subtypes and authors indicate different cellular mechanisms that lead to megalencephalic leukoencephalopathy pathogenesis. (PMID:25044933)
• GlialCAM is able to interact with all CLC channels tested in this study, targeting them to cell junctions and activating them by stabilizing the open configuration of the common gate (PMID:25185546)
• The extracellular domain of GlialCAM is necessary for cell junction targeting and for mediating interactions with itself or with MLC1 and ClC-2. (PMID:26033718)
• The suppressive roles of HEPACAM in NSCLC. (PMID:26392113)
• Due to the ability to reactivate expression of hepaCAM and inhibit growth of bladder cancer cells, AZAC may represent an effective treatment for bladder cancer. (PMID:26677113)
• HepaCAM proteins were significantly decreased in bladder carcinoma. Low hepaCAM was not statistically associated with clinicopathological characteristics of the patients. HepaCAM overexpression activated caspase 3/8/9, downregulated poly-ADP ribose polymerase and p-SMAD2/3, and decreased apoptosis. (PMID:26873485)
• Out of 20 patients, macrocephaly, classic MRI features, motor development delay and cognitive impairment were detected in 20(100%), 20(100%), 17(85%) and 4(20%) patients, respectively. 20(100%) were clinically diagnosed with MLC. 19(95%) were genetically diagnosed with 10 novel mutations in MLC1, MLC1 and GlialCAM mutations were identified in 15 and 4 patients, respectively (PMID:27322623)
• In a group of Egyptian patients with megalencephalic leukoencephalopathy, novel mutations were identified in HEPACAM. (PMID:27389245)
• hepaCAM associates with connexin 43, a main component of gap junctions, and enhances connexin 43 localization to the plasma membrane at cellular junctions. (PMID:27819278)
• DNMT1 up-regulation induced by IL-6/STAT3 signaling was indispensable for IL-6-mediated hepaCAM loss in renal cell carcinoma (RCC) cell lines ACHN and 769-P, while DNMT3b up-regulation was crucial for hepaCAM loss in A498. (PMID:28093267)
• HepaCAM depletion was discovered in bladder cancer tissues compared with adjacent normal tissues, and the decreased level was associated with the degradation of FoxO3. (PMID:28229220)
• this study revealed that hepaCAM was downregulated in CRC tissues and cell lines. Overexpression of hepaCAM inhibited CRC cell proliferation, migration, and invasion in vitro. Furthermore, the tumorigenesis assay showed that increased expression of hepaCAM suppressed CRC tumor growth and metastasis in vivo. (PMID:28244854)
• On the whole, this study indicates that HepaCAM potentially represents a therapeutic target and PF3084014 may prove to a promising agent for use in the treatment of refractory prostate cancer. (PMID:29658567)
• The results suggest that HepaCAM and its cytoplasmic domain suppress the nuclear translocation of AR via Ran in prostate cancer (PCa). The cytoplasmic domain of HepaCAM may serve as a novel target for therapy in PCa. (PMID:30664187)
• Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1-Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been repor (PMID:31372844)
• Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies. (PMID:31960914)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hepacama	ENSDARG00000056934
danio_rerio	HEPACAM	ENSDARG00000112032
mus_musculus	Hepacam	ENSMUSG00000046240
rattus_norvegicus	Hepacam	ENSRNOG00000009219

Paralogs (24): CEACAM21 (ENSG00000007129), CEACAM7 (ENSG00000007306), CEACAM1 (ENSG00000079385), CEACAM6 (ENSG00000086548), CEACAM4 (ENSG00000105352), CEACAM5 (ENSG00000105388), PSG8 (ENSG00000124467), CEACAM8 (ENSG00000124469), PSG6 (ENSG00000170848), CEACAM3 (ENSG00000170956), PSG9 (ENSG00000183668), CEACAM19 (ENSG00000186567), HEPACAM2 (ENSG00000188175), PSG5 (ENSG00000204941), CEACAM18 (ENSG00000213822), CEACAM16 (ENSG00000213892), VSTM5 (ENSG00000214376), PSG3 (ENSG00000221826), PSG7 (ENSG00000221878), PSG1 (ENSG00000231924), PSG2 (ENSG00000242221), PSG11 (ENSG00000243130), PSG4 (ENSG00000243137), CEACAM20 (ENSG00000273777)

Protein

Protein identifiers

Hepatic and glial cell adhesion molecule — Q14CZ8 (reviewed: Q14CZ8)

Alternative names: Hepatocyte cell adhesion molecule

All UniProt accessions (2): A0A994J4I1, Q14CZ8

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulating cell motility and cell-matrix interactions. May inhibit cell growth through suppression of cell proliferation. In glia, associates and targets CLCN2 at astrocytic processes and myelinated fiber tracts where it may regulate transcellular chloride flux involved in neuron excitability.

Subunit / interactions. Homodimer. Dimer formation occurs predominantly through cis interactions on the cell surface. Part of a complex containing MLC1, TRPV4, AQP4 and ATP1B1. Interacts with CLCN2.

Subcellular location. Cytoplasm. Cell membrane.

Post-translational modifications. N-glycosylated.

Disease relevance. Megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A) [MIM:613925] A neurodegenerative disorder characterized by infantile-onset macrocephaly and later onset of motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. The brain appears swollen on magnetic resonance imaging with white-matter abnormalities and subcortical cysts, in all stages of the disease. The disease is caused by variants affecting the gene represented in this entry. Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B) [MIM:613926] A neurodegenerative disorder characterized by infantile-onset of macrocephaly and mildly delayed motor development associated with white-matter abnormalities on brain magnetic resonance imaging. The phenotype is milder that MLC2A, with better preserved cerebellar white matter and no subcortical cysts outside the temporal region. On follow-up, patients show normal or almost normal motor function. Some patients have normal intelligence, whereas others have a significant cognitive deficiency. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The cytoplasmic domain plays an important role in regulation of cell-matrix adhesion and cell motility.

Induction. Down-regulated in 20 out of 23 of hepatocellular carcinoma (HCC) samples and is undetectable in 5 HCC cell lines tested.

Miscellaneous. Antibodies that recognize both Epstein-Barr virus EBNA1 and HEPACAM/GlialCAM can be produced when B cells undergo somatic hypermutations. HEPACAM/GlialCAM can thus become an autoantigen for self-directed autoimmunity and possibly contribute to the events leading to multiple sclerosis.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14CZ8-1	1	yes
Q14CZ8-2	2

RefSeq proteins (2): NP_001397972, NP_689935* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR052280	HEPACAM_domain	Family

Pfam: PF07686, PF13927

UniProt features (37 total): sequence variant 13, glycosylation site 4, sequence conflict 4, modified residue 3, splice variant 2, topological domain 2, domain 2, compositionally biased region 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7UQC	X-RAY DIFFRACTION	2.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14CZ8-F1	72.60	0.47

Antibody-complex structures (SAbDab): 1 — 7UQC

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 (3): 278, 350, 377

Disulfide bonds (1): 168–217

Glycosylation sites (4): 35, 138, 167, 189

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 190 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, YAATNRNNNYNATT_UNKNOWN, CMYB_01, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_CELL_CYCLE, OCT1_07, MAF_Q6, LEF1_Q6, POU3F2_02, GOCC_CELL_CELL_JUNCTION, CTTTGTA_MIR524, TGCCTTA_MIR124A, ISRE_01

GO Biological Process (4): immune response (GO:0006955), cell adhesion (GO:0007155), regulation of cell cycle (GO:0051726), protein localization to cell-cell junction (GO:0150105)

GO Molecular Function (0):

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), astrocyte end-foot (GO:0097450), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
immune system process	1
response to stimulus	1
cellular process	1
cell cycle	1
regulation of cellular process	1
protein localization to cell junction	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
anchoring junction	1
astrocyte projection	1

Protein interactions and networks

STRING

646 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEPACAM	KCNJ10	P78508	706
HEPACAM	LRRC8A	Q8IWT6	695
HEPACAM	CLCN2	P51788	604
HEPACAM	CLCN7	P51798	593
HEPACAM	GJA1	P17302	592
HEPACAM	TRPV4	Q9HBA0	590
HEPACAM	CDH1	P12830	579
HEPACAM	CNTNAP1	P78357	546
HEPACAM	ALDH1L1	O75891	532
HEPACAM	GPR37L1	O60883	520
HEPACAM	GJB6	O95452	507
HEPACAM	LRRC8C	Q8TDW0	507
HEPACAM	PRDX6	P30041	503
HEPACAM	CAV1	Q03135	478
HEPACAM	LRRC8E	Q6NSJ5	475

IntAct

9 interactions, top by confidence:

A	B	Type	Score
ECE1	HEPACAM	psi-mi:“MI:0915”(physical association)	0.370
	AQP4	psi-mi:“MI:0914”(association)	0.350
	HEPACAM	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
C1orf87	SNX2	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): HEPACAM (Affinity Capture-MS), HEPACAM (Affinity Capture-MS), HEPACAM (Affinity Capture-MS), HEPACAM (Affinity Capture-MS), HEPACAM (Affinity Capture-MS), HEPACAM (Affinity Capture-MS)

ESM2 similar proteins: A0JNA2, A4FUY1, C0HL12, O14514, O19131, O60241, O75325, P0C5H6, P15151, P32506, P32507, P70225, P98095, Q05BQ1, Q13477, Q14626, Q14CZ8, Q29RN8, Q3UHD1, Q4V9Z5, Q53EL9, Q5DRQ8, Q5R7Y0, Q5RF19, Q5STE3, Q63148, Q64385, Q6AX42, Q6BAA4, Q6MZW2, Q6UWL2, Q6UWL6, Q6UXD5, Q6WN34, Q7TSK2, Q7TSU7, Q8BHA1, Q8BQC3, Q8CGM1, Q8IVU1

Diamond homologs: A4FUY1, A6QQC6, A8MVW5, D3YXG0, D3ZB51, D3ZQE1, E9PZ19, O08775, P13595, P13596, P16573, P31809, P35968, P52583, Q00889, Q14CZ8, Q3KPI0, Q4VAH7, Q52KR2, Q62845, Q640R3, Q69Z26, Q9D2Z1, Q9HBG7, Q9UPX0, Q5STE3, Q63111, Q640U3, Q6MZW2, Q00888, Q8BFR2, Q8N475, A6NDA9, G5EGI7, O02827, O95428, P0C192, P0C5H6, P0CC10, P14781

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	10
Uncertain significance	175
Likely benign	70
Benign	22

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1068633	NM_152722.5(HEPACAM):c.523A>T (p.Lys175Ter)	Pathogenic
1335090	NM_152722.5(HEPACAM):c.298C>T (p.Arg100Ter)	Pathogenic
1437100	NM_152722.5(HEPACAM):c.520_541del (p.Gly173_Thr174insTer)	Pathogenic
2094131	NM_152722.5(HEPACAM):c.100dup (p.Val34fs)	Pathogenic
30914	NM_152722.5(HEPACAM):c.587C>A (p.Ser196Tyr)	Pathogenic
30915	NM_152722.5(HEPACAM):c.789G>A (p.Trp263Ter)	Pathogenic
30917	NM_152722.5(HEPACAM):c.631G>A (p.Asp211Asn)	Pathogenic
30921	NM_152722.5(HEPACAM):c.274C>T (p.Arg92Trp)	Pathogenic
3686032	NM_152722.5(HEPACAM):c.513del (p.Asn172fs)	Pathogenic
419081	NM_152722.5(HEPACAM):c.980del (p.Pro327fs)	Pathogenic
4531823	NM_152722.5(HEPACAM):c.265G>C (p.Gly89Arg)	Pathogenic
1335946	NM_152722.5(HEPACAM):c.285T>G (p.Tyr95Ter)	Likely pathogenic
191275	NM_152722.5(HEPACAM):c.757_759del (p.Leu253del)	Likely pathogenic
2136279	NM_152722.5(HEPACAM):c.863del (p.Arg288fs)	Likely pathogenic
30918	NM_152722.5(HEPACAM):c.292C>T (p.Arg98Cys)	Likely pathogenic
30920	NM_152722.5(HEPACAM):c.266G>A (p.Gly89Asp)	Likely pathogenic
3233388	NM_152722.5(HEPACAM):c.949-2A>G	Likely pathogenic
433199	NM_152722.5(HEPACAM):c.442C>T (p.Pro148Ser)	Likely pathogenic
444277	NM_152722.5(HEPACAM):c.85+1G>A	Likely pathogenic
4529564	NM_152722.5(HEPACAM):c.286C>T (p.Arg96Ter)	Likely pathogenic
590970	NM_152722.5(HEPACAM):c.359A>G (p.Tyr120Cys)	Likely pathogenic

SpliceAI

1519 predictions. Top by Δscore:

Variant	Effect	Δscore
11:124923721:AAACT:A	donor_loss	1.0000
11:124923722:AACTC:A	donor_loss	1.0000
11:124923723:ACTC:A	donor_loss	1.0000
11:124923725:TCA:T	donor_loss	1.0000
11:124923726:CA:C	donor_loss	1.0000
11:124923727:A:AC	donor_gain	1.0000
11:124923727:ACT:A	donor_loss	1.0000
11:124923728:C:CA	donor_gain	1.0000
11:124923728:CT:C	donor_gain	1.0000
11:124923728:CTGTA:C	donor_gain	1.0000
11:124924726:ACC:A	donor_loss	1.0000
11:124924755:C:CA	donor_gain	1.0000
11:124924756:C:A	donor_gain	1.0000
11:124922456:CTG:C	acceptor_gain	0.9900
11:124922744:CCTT:C	donor_gain	0.9900
11:124923728:CTG:C	donor_gain	0.9900
11:124923728:CTGT:C	donor_gain	0.9900
11:124923729:TGTA:T	donor_gain	0.9900
11:124924017:C:CT	acceptor_gain	0.9900
11:124924017:C:T	acceptor_gain	0.9900
11:124925067:GGT:G	acceptor_gain	0.9900
11:124925069:TCTGT:T	acceptor_loss	0.9900
11:124925070:C:CC	acceptor_gain	0.9900
11:124925070:CT:C	acceptor_loss	0.9900
11:124925084:CCA:C	acceptor_gain	0.9900
11:124925085:C:CT	acceptor_gain	0.9900
11:124925085:C:T	acceptor_gain	0.9900
11:124922457:TG:T	acceptor_gain	0.9800
11:124922459:C:CC	acceptor_gain	0.9800
11:124922815:TTTCC:T	acceptor_loss	0.9800

AlphaMissense

2669 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:124923787:G:C	C217W	1.000
11:124923788:C:G	C217S	1.000
11:124923789:A:G	C217R	1.000
11:124923789:A:T	C217S	1.000
11:124923795:A:C	Y215D	1.000
11:124923833:A:G	L202P	1.000
11:124923898:C:A	W180C	1.000
11:124923898:C:G	W180C	1.000
11:124923900:A:G	W180R	1.000
11:124923900:A:T	W180R	1.000
11:124923934:G:C	C168W	1.000
11:124923935:C:G	C168S	1.000
11:124923936:A:G	C168R	1.000
11:124923936:A:T	C168S	1.000
11:124924739:A:G	L139P	1.000
11:124924835:A:G	L107P	1.000
11:124924948:C:A	W69C	1.000
11:124924948:C:G	W69C	1.000
11:124924950:A:G	W69R	1.000
11:124924950:A:T	W69R	1.000
11:124923775:G:C	N221K	0.999
11:124923775:G:T	N221K	0.999
11:124923788:C:T	C217Y	0.999
11:124923806:T:A	D211V	0.999
11:124923833:A:T	L202H	0.999
11:124923899:C:G	W180S	0.999
11:124923935:C:T	C168Y	0.999
11:124924790:A:T	V122D	0.999
11:124924797:A:C	Y120D	0.999
11:124924911:A:G	S82P	0.999

dbSNP variants (sampled 300 via entrez): RS1000069604 (11:124926876 ATT>A,AT,ATTT), RS1000602269 (11:124922166 A>C,G), RS1000755140 (11:124928490 T>A,C,G), RS1000899669 (11:124919743 TGGA>T), RS1000949747 (11:124931669 A>T), RS1001142053 (11:124921954 G>A), RS1001269056 (11:124933391 G>A), RS1001543144 (11:124919418 C>T), RS1001709646 (11:124926781 A>C,G), RS1001760543 (11:124926980 T>C), RS1002006325 (11:124920847 G>A,C), RS1002078652 (11:124924187 CACTG>C), RS1002425631 (11:124938018 G>A), RS1002504264 (11:124928922 C>T), RS1002625486 (11:124919040 T>C,G)

Disease associations

OMIM: gene MIM:611642 | disease phenotypes: MIM:613925, MIM:613926, MIM:604004

GenCC curated gene-disease

Disease	Classification	Inheritance
megalencephalic leukoencephalopathy with subcortical cysts 2A	Strong	Autosomal recessive
megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability	Strong	Autosomal dominant
macrocephaly-autism syndrome	Supportive	Autosomal dominant
megalencephalic leukoencephalopathy with subcortical cysts	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability	Definitive	AD
megalencephalic leukoencephalopathy with subcortical cysts 2A	Definitive	AR

Mondo (7): megalencephalic leukoencephalopathy with subcortical cysts 2A (MONDO:0013490), megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (MONDO:0013491), megalencephalic leukoencephalopathy with subcortical cysts 1 (MONDO:0024555), megalencephalic leukoencephalopathy with subcortical cysts (MONDO:0011391), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), macrocephaly-autism syndrome (MONDO:0011537)

Orphanet (3): Megalencephalic leukoencephalopathy with subcortical cysts (Orphanet:2478), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000957	Cafe-au-lait spot
HP:0001012	Multiple lipomas
HP:0001054	Numerous nevi
HP:0001177	Preaxial hand polydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001355	Megalencephaly
HP:0001397	Hepatic steatosis
HP:0001829	Foot polydactyly
HP:0002007	Frontal bossing
HP:0002015	Dysphagia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002861_2	Breast cancer (survival)	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C565342	Macrocephaly Autism Syndrome (supp.)
C536141	Megalencephalic leukoencephalopathy with subcortical cysts (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
bisphenol A	affects expression, affects cotreatment, increases methylation	2
Benzo(a)pyrene	decreases methylation, increases methylation, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Catechin	affects cotreatment, decreases expression	1
Lead	affects expression	1
N-Nitrosopyrrolidine	increases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Dronabinol	increases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06462430	Not specified	RECRUITING	PTEN Hamartoma Tumor Syndrome Pediatric Patient Registry
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)