HEPACAM

Chr 11ARAD

hepatic and glial cell adhesion molecule

Also known as: GlialCAM, MLC2A, MLC2B

NCBI Gene: 220296ENSG00000165478UniProt: Q14CZ8

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. [provided by RefSeq, Jul 2011]

Primary Disease Associations & Inheritance

Megalencephalic leukoencephalopathy with subcortical cysts 2AMIM #613925
AR
Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual developmentMIM #613926
AD
386
ClinVar variants
82
Pathogenic / LP
0.87
pLI score
0
Active trials
Clinical Summary— HEPACAM
🧬
Gene-Disease Validity (ClinGen)
megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
82 Pathogenic / Likely Pathogenic· 181 VUS of 386 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.41LOEUF
pLI 0.868
Z-score 3.16
OE 0.13 (0.05–0.41)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.59Z-score
OE missense 0.69 (0.60–0.79)
145 obs / 209.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.05–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.60–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 2 / 15.4Missense obs/exp: 145 / 209.9Syn Z: 0.19

ClinVar Variant Classifications

386 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic14
VUS181
Likely Benign80
Benign22
Conflicting21
68
Pathogenic
14
Likely Pathogenic
181
VUS
80
Likely Benign
22
Benign
21
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
4
61
0
68
Likely Pathogenic
3
6
5
0
14
VUS
0
129
50
2
181
Likely Benign
0
8
33
39
80
Benign
0
4
14
4
22
Conflicting
—21
Total615116345386

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HEPACAM · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Megalencephalic leukoencephalopathy with subcortical cysts 2A

MIM #613925

Molecular basis of disorder known

Autosomal recessive

Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development

MIM #613926

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — HEPACAM
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expression and clinical significance of hepaCAM and VEGF in urothelial carcinoma.
Yang S et al.·World J Urol
2010
Panobinostat reverses HepaCAM gene expression and suppresses proliferation by increasing histone acetylation in prostate cancer.
Chen E et al.·Gene
2022
Megalencephalic leukoencephalopathy with subcortical cysts: a multicenter Italian experience.
Sartorelli J et al.·Neurol Sci
2026
The SMAD2/3 pathway is involved in hepaCAM-induced apoptosis by inhibiting the nuclear translocation of SMAD2/3 in bladder cancer cells.
Wang X et al.·Tumour Biol
2016
Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect.
Abdel-Salam GM et al.·Metab Brain Dis
2016Cohort
[Analysis of HEPACAM mutations in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts].
Guo MM et al.·Zhonghua Er Ke Za Zhi
2012
Comprehensive molecular biomarker identification in breast cancer brain metastases.
Schulten HJ et al.·J Transl Med
2017
Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.
López-Hernández T et al.·Am J Hum Genet
2011
A homozygous missense variant in the MLC1 gene underlies megalencephalic leukoencephalopathy with subcortical cysts in large kindred: Heterozygous carriers show seizure and mild motor function deterioration.
Ain Ul Batool S et al.·Am J Med Genet A
2022
Frequent alterations of LOH11CR2A, PIG8 and CHEK1 genes at chromosomal 11q24.1-24.2 region in breast carcinoma: clinical and prognostic implications.
Sinha S et al.·Mol Oncol
2011
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Loss of hepaCAM inhibits cholesterol biosynthesis and impairs learning and memory in mice.
Qiu Z et al.·Brain Res
2026
Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model.
Jin S et al.·Sci Adv
2024🔓 Open AccessFunctional
Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A.
Kaur N et al.·Neurogenetics
2024
Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation.
Jin S et al.·Nat Commun
2023🔓 Open Access
[Corrigendum] HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain.
Deng Q et al.·Mol Med Rep
2022🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools