LCT

Summary

LCT (lactase, HGNC:6530) is a protein-coding gene on chromosome 2q21.3, encoding Lactase/phlorizin hydrolase (P09848). Broad specificity glycosidase of the intestinal brush border membrane that hydrolyzes lactose, the main sugar in mammalian milk, to produce D-glucose and D-galactose.

The protein encoded by this gene belongs to the glycosyl hydrolase 1 family of proteins. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme is integral to the plasma membrane and has both phlorizin hydrolase activity and lactase activity. Mutations in this gene are associated with congenital lactase deficiency. Polymorphisms in this gene are associated with lactase persistence, in which intestinal lactase activity persists at childhood levels into adulthood.

Source: NCBI Gene 3938 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital lactase deficiency (Strong, GenCC)
• GWAS associations: 13
• Clinical variants (ClinVar): 977 total — 32 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002299

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6530
Approved symbol	LCT
Name	lactase
Location	2q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115850
Ensembl biotype	protein_coding
OMIM	603202
Entrez	3938

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000264162, ENST00000452974

RefSeq mRNA: 1 — MANE Select: NM_002299 NM_002299

CCDS: CCDS2178

Canonical transcript exons

ENST00000264162 — 17 exons

Exon	Start	End
ENSE00000776570	135800607	135800809
ENSE00000776571	135803930	135804128
ENSE00000776572	135804767	135805057
ENSE00000776573	135807128	135807396
ENSE00000776576	135812311	135812956
ENSE00001008768	135808443	135809993
ENSE00001602826	135817341	135818061
ENSE00001630333	135794641	135794775
ENSE00001653704	135787850	135788544
ENSE00001659892	135823901	135824003
ENSE00001660765	135833111	135833190
ENSE00001667885	135790658	135790881
ENSE00001728878	135789571	135789798
ENSE00001731451	135829593	135829676
ENSE00001777620	135822020	135822098
ENSE00002202258	135836530	135837184
ENSE00003515081	135798029	135798138

Expression profiles

Bgee: expression breadth broad, 26 present calls, max score 99.75.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.0413 / max 2844.6531, expressed in 19 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30771	3.0317	19
30769	0.0096	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.75	gold quality
duodenum	UBERON:0002114	95.00	gold quality
jejunum	UBERON:0002115	76.10	gold quality
ileal mucosa	UBERON:0000331	73.75	gold quality
tibialis anterior	UBERON:0001385	69.67	silver quality
pancreatic ductal cell	CL:0002079	67.81	silver quality
mucosa of urinary bladder	UBERON:0001259	67.13	gold quality
small intestine	UBERON:0002108	60.22	gold quality
oocyte	CL:0000023	59.64	gold quality
endothelial cell	CL:0000115	59.33	gold quality
diaphragm	UBERON:0001103	58.88	gold quality
hair follicle	UBERON:0002073	56.91	gold quality
decidua	UBERON:0002450	56.55	gold quality
deltoid	UBERON:0001476	55.86	gold quality
sperm	CL:0000019	55.14	gold quality
male germ cell	CL:0000015	54.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	53.59	gold quality
upper leg skin	UBERON:0004262	52.81	silver quality
epithelial cell of pancreas	CL:0000083	52.55	gold quality
thymus	UBERON:0002370	51.58	gold quality
quadriceps femoris	UBERON:0001377	51.00	gold quality
bone marrow cell	CL:0002092	50.97	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
metanephric glomerulus	UBERON:0004736	49.61	gold quality
buccal mucosa cell	CL:0002336	49.48	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CDX2, ENO1, FOXA1, FOXA2, GATA4, GATA5, GATA6, GTF3A, HIF1A, HNF1A, HNF4A, HOXC11, NFKB, NR1I2, ONECUT1, POU1F1, POU2F1, TBPL1, TCF3, YBX3, ZNF160

miRNA regulators (miRDB)

31 targeting LCT, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-7106-3P	97.33	65.33	644
HSA-MIR-3667-5P	97.16	64.87	591
HSA-MIR-4714-5P	97.04	67.76	955
HSA-MIR-4680-5P	96.43	67.15	893

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. (PMID:12015606)
• Brm complex mutants suppress the DmcycE(JP) phenotype by increasing S phases w/o affecting DmcycE protein levels. DmcycE physically interacts with Brm & Snr1 in vivo. The Brm complex inhibits S phase by acting downstream of DmcycE protein accumulation. (PMID:12093739)
• centrosome overduplication still occurs in skpA-; cycE- mutant animals, demonstrating that high cyclin E levels are not necessary for centrosome overduplication (PMID:12730292)
• we link the CSN to the degradation of Cyclin E, which promotes the G1-S transition in the cell cycle and then is rapidly degraded by the ubiquitin-proteasome pathway (PMID:12737805)
• asymmetric divisions are due to upregulation of Cyclin E in late ganglion mother cells (PMID:14973280)
• phosphorylation and degradation of Dup protein at G1/S requires cyclin E/CDK2 (PMID:15342466)
• string(cdc25) and cyclin E control patterned histone expression at different stages of Drosophila embryonic development. (PMID:15355790)
• critical role for CycE in regulating cell fate in segment-specific neural lineages. (PMID:15580266)
• cyclin E functions downstream of the homeotic genes largly independently of its role in proliferation (PMID:15632940)
• Cell cycle diversity involves differential regulation of Cyclin E activity in the Drosophila bristle cell lineage. (PMID:15829522)
• The most significant cyclin E alteration is post-translational cleavage of full-length cyclin E into low molecular weight forms that are hyperactive compared to the 50-kDa, full-length protein and correlate with increasing stage of breast cancer. (PMID:16637514)
• Fondue is a major hemolymph protein required for efficient clotting in Drosophila (PMID:16690050)
• APC/C-Fzr activity is periodically inhibited by CycE-Cdk2, to prevent relicensing in S-phase cells. (PMID:18559483)
• Wg signaling is important for the expression of cyclin E in the sensory organ precursor (SOP) cells through two conserved TCF binding sites. (PMID:18606221)
• Minus contributes to cell cycle regulation in part by selectively controlling turnover of Cyclin E (PMID:19723762)
• analysis of Abdominal-A mediated repression of Cyclin E expression during cell-fate specification in the Drosophila central nervous system (PMID:19799999)
• CycE inhibits the function of Prospero and facilitates its cortical localization, which is critical for inducing stem cell behaviour. (PMID:19914234)
• follicular stem cell function was substantially restored by expressing either excess DE-cadherin or excess E2F1/DP, the transcription factor normally activated by CycE-Cdk2 phosphorylation of retinoblastoma proteins (PMID:19966222)
• The chromatin-remodeling protein Osa interacts with CyclinE in Drosophila eye imaginal discs. (PMID:20008573)
• This work provides in vivo genetic evidence for p53-mediated integration of metabolic stress signals, which modulate the activity of the ubiquitin-proteasome system to degrade cyclin E protein and thereby impose cell cycle arrest. (PMID:20176921)
• p53-mediated regulation of ectopic neural stem cells (NSC) self-renewal through the Ago/Cyc E axis becomes particularly important when NSC homeostasis is perturbed. (PMID:22140513)
• CycE and Cdk2 are required for germline stem cell proliferation. (PMID:23293285)
• We further detected that reduced level of GRK2 induced a small cell cycle arrest at G2/M phase by enhancing the expression of cyclin A, B1, and E (PMID:23460259)
• we provide genetic evidences, that the Ama-Nrt-Abl-pathway regulates CycE expression by altering the function of the Hippo effector Yorkie in embryonic NBs (PMID:27015425)
• we show that Ewg repression of Cyclin E expression is required for the arrest of myoblast proliferation and initiate myoblast fusion and terminal differentiation (PMID:27039019)
• These findings suggest that spatiotemporal expression of transcription factor Sd induces differential growth regulation by Yki during wing disc development, highlighting coordination between Yki and CycE to control growth and maintain homeostasis. (PMID:28143945)
• Apt-mediated expression of Hh and cyclin E can direct proliferation of Hh-expressing cells and simultaneous growth, patterning and differentiation of Hh-recipient cells. (PMID:28963499)
• These findings reveal a Gcm-Apt-CycE axis that regulates neuroblast and glia cell differentiation. (PMID:29625112)
• Cyclin E and Cdk1 regulate the termination of germline transit-amplification process in Drosophila testis. (PMID:32573329)
• These data clearly demonstrate that the proregion of pro-LPH is an intramolecular chaperone that is critically essential in facilitating the folding of the intermediate form LPH beta(initial) in the context of the pro-LPH polypeptide. (PMID:11751874)
• demonstrate that GATA-5 and HNF-1alpha physically associate both in vivo and in vitro and that this interaction is necessary for cooperative activation of the lactase-phlorizin hydrolase promoter (PMID:12011060)
• Results suggest that repression of lactase-phlorizin hydrolase (LPH) gene expression is released in cells that synthesize Cdx-2, such as those in the intestinal epithelium. (PMID:12459179)
• A lactase persistent variant enhances lactase promoter activity in vitro. (PMID:12915462)
• Stable overexpression of pancreatic duodenal homeobox-1 results in repression of the endogenous human lactase-phlorizin hydrolase gene in differentiated Caco-2 cells (PMID:15107297)
• GATA-4 is a key regulator of LPH gene expression that may function through an evolutionarily conserved mechanism involving cooperativity with an HNF-1alpha and/or a GATA-specific pathway independent of HNF-1alpha. (PMID:15178553)
• The adjustments for age, height, weight, smoking, alcohol consumption, and physical exercise in the multiple regression analysis did not reveal any big relationships between the lactase genotypes and BMDs at lumbar, femoral neck or total hip sites. (PMID:15365657)
• the binding of Oct-1 to the T-13,910 lactase variant directs increased lactase promoter activity and this might provide an explanation for the lactase persistence phenotype in the human population (PMID:16301215)
• The molecular background of congenital lactase deficiency via characterization of five distinct mutations in the coding region of the lactase (LCT) gene was reported. (PMID:16400612)
• lactase-phlorizin hydrolase C/C-13910 genotype was not associated with mean growth speed or final mean body height; however, it contributed significantly to milk product consumption and dietary calcium intake from childhood into young adulthood (PMID:17015546)
• cohort study of lactose digester and non-digester Sudanese volunteers shows there is no association of -13910*T or the A haplotype with lactase persistence (PMID:17120047)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	lct	ENSDARG00000060671
danio_rerio	LCT	ENSDARG00000092404
mus_musculus	Lct	ENSMUSG00000026354
rattus_norvegicus	Lct	ENSRNOG00000003681
drosophila_melanogaster	CG9701	FBGN0036659
caenorhabditis_elegans		WBGENE00016848
caenorhabditis_elegans		WBGENE00017103

Paralogs (4): KL (ENSG00000133116), KLB (ENSG00000134962), LCTL (ENSG00000188501), GBA3 (ENSG00000249948)

Protein

Protein identifiers

Lactase/phlorizin hydrolase — P09848 (reviewed: P09848)

Alternative names: Lactase/glycosylceramidase

All UniProt accessions (2): P09848, H0Y4E4

UniProt curated annotations — full annotation on UniProt →

Function. Broad specificity glycosidase of the intestinal brush border membrane that hydrolyzes lactose, the main sugar in mammalian milk, to produce D-glucose and D-galactose. The mature protein is composed of two domains that catalyze the hydrolysis of beta-glucopyranosides and beta-galactopyranosides, with a preference for hydrophilic aglycones (in lactose and cellobiose) for one domain and hydrophobic aglycones (in phlorizin and glycosylceramides) for the other.

Subunit / interactions. Homodimer.

Subcellular location. Apical cell membrane.

Tissue specificity. Specifically expressed in small intestine.

Post-translational modifications. N-glycosylated.

Disease relevance. Congenital lactase deficiency (COLACD) [MIM:223000] Autosomal recessive, rare and severe gastrointestinal disorder. It is characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. An almost total lack of LCT activity is found in jejunal biopsy material of patients with congenital lactase deficiency. Opposite to congenital lactase deficiency, also known as lactose intolerance, is the most common enzyme deficiency worldwide. It is caused by developmental down-regulation of lactase activity during childhood or early adulthood. The decline of lactase activity is a normal physiological phenomenon; however, the majority of Northern Europeans have the ability to maintain lactase activity and digest lactose throughout life (lactase persistence). The down-regulation of lactase activity operates at the transcriptional level and it is associated with a noncoding variation in the MCM6 gene, located in the upstream vicinity of LCT. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The glycosyl hydrolase-1 3/region III carries the phlorizin hydrolase/glycosylceramidase activities. The glycosyl hydrolase-1 4/region IV carries the lactase activity.

Similarity. Belongs to the glycosyl hydrolase 1 family.

RefSeq proteins (1): NP_002290* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001360	Glyco_hydro_1	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR018120	Glyco_hydro_1_AS	Active_site
IPR033132	GH_1_N_CS	Conserved_site

Pfam: PF00232

Enzyme classification (BRENDA):

• EC 3.2.1.108 — lactase (BRENDA: 8 organisms, 56 substrates, 12 inhibitors, 21 Km, 6 kcat entries)
• EC 3.2.1.62 — glycosylceramidase (BRENDA: 17 organisms, 120 substrates, 61 inhibitors, 72 Km, 17 kcat entries)
• EC 3.7.1.4 — phloretin hydrolase (BRENDA: 11 organisms, 50 substrates, 39 inhibitors, 18 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

66 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-O-BETA-D-GALACTOPYRANOSYL-D-GLUCOPYRANOSIDE	5.1–41.7	10
PHLORETIN	0.0028–0.289	9
LACTOSE	5.1–30	8
PHLORIZIN	0.002–0.44	6
LACTOSE	8.8–30	4
PHLORIZIN	0.002–0.44	3
2-CHLORO-4-NITROPHENYL BETA-CELLOBIOSIDE	7–22.7	3
4-O-BETA-D-GLUCOPYRANOSYL-D-GLUCOPYRANOSIDE	1.1–2.78	3
CELLOBIOSE	2.78–4.4	2
GALACTOSYLCERAMIDE	0.065–0.51	2
N-PALMITOYLDIHYDROCEREBROSIDE	0.73–1.12	2
P-NITROPHENYL-BETA-CELLOBIOSIDE	0.542–18.13	2
P-NITROPHENYL-BETA-LACTOSIDE	1.67–21.62	2
P-NITROPHENYL-BETA-MALTOSIDE	2.82–5.12	2
LACTOSE	16–21.8	2

Catalyzed reactions (Rhea), 12 shown:

• lactose + H2O = beta-D-galactose + D-glucose (RHEA:10076)
• D-cellobiose + H2O = beta-D-glucose + D-glucose (RHEA:30679)
• phlorizin + H2O = phloretin + beta-D-glucose (RHEA:69639)
• quercetin 4’-O-beta-D-glucoside + H2O = quercetin + beta-D-glucose (RHEA:69647)
• quercetin 3-O-beta-D-glucoside + H2O = quercetin + beta-D-glucose (RHEA:69655)
• kaempferol 3-O-beta-D-glucoside + H2O = kaempferol + beta-D-glucose (RHEA:69659)
• luteolin 7-O-beta-D-glucoside + H2O = luteolin + beta-D-glucose (RHEA:69663)
• luteolin 4’-O-beta-D-glucoside + H2O = luteolin + beta-D-glucose (RHEA:69667)
• (2S)-naringenin 7-O-beta-D-glucoside + H2O = (2S)-naringenin + beta-D-glucose (RHEA:69671)
• eriodictyol-7-O-beta-D-glucoside + H2O = (S)-eriodictyol + beta-D-glucose (RHEA:69675)
• apigenin 7-O-beta-D-glucoside + H2O = apigenin + beta-D-glucose (RHEA:69679)
• daidzein 7-O-beta-D-glucoside + H2O = daidzein + beta-D-glucose + H(+) (RHEA:69683)

UniProt features (42 total): glycosylation site 15, sequence variant 7, region of interest 6, active site 4, topological domain 2, mutagenesis site 2, signal peptide 1, propeptide 1, compositionally biased region 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09848-F1	86.63	0.66

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 1065 (proton donor; for phlorizin hydrolase/glycosylceramidase activity); 1273 (nucleophile; for phlorizin hydrolase/glycosylceramidase activity); 1538 (proton donor; for lactase activity); 1749 (nucleophile; for lactase activity)

Glycosylation sites (15): 42, 368, 418, 512, 821, 934, 946, 989, 1174, 1340, 1508, 1656, 1672, 1761, 1814

Mutagenesis-validated functional residues (2):

Position	Phenotype
1273	no effect on lactase activity. decreased phlorizin hydrolase activity. no effect on localization to the plasma membrane.
1749	loss of lactase activity. no effect on phlorizin hydrolase activity. no effect on localization to the plasma membrane.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-189085	Digestion of dietary carbohydrate
R-HSA-5659898	Intestinal saccharidase deficiencies
R-HSA-1643685	Disease
R-HSA-5663084	Diseases of carbohydrate metabolism
R-HSA-5668914	Diseases of metabolism
R-HSA-8935690	Digestion
R-HSA-8963743	Digestion and absorption

MSigDB gene sets: 140 (showing top): VALK_AML_WITH_FLT3_ITD, GOBP_CERAMIDE_CATABOLIC_PROCESS, GOBP_OLIGOSACCHARIDE_METABOLIC_PROCESS, REACTOME_DIGESTION_OF_DIETARY_CARBOHYDRATE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_OLIGOSACCHARIDE_CATABOLIC_PROCESS, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, GOBP_GLYCOLIPID_CATABOLIC_PROCESS, MORF_ZNF10, RGTTAMWNATT_HNF1_01, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (5): lactose catabolic process (GO:0005990), glycosylceramide catabolic process (GO:0046477), quercetin catabolic process (GO:1901733), cellobiose catabolic process (GO:2000892), carbohydrate metabolic process (GO:0005975)

GO Molecular Function (11): lactase activity (GO:0000016), galactosylceramidase activity (GO:0004336), glucosylceramidase activity (GO:0004348), beta-glucosidase activity (GO:0008422), protein homodimerization activity (GO:0042803), cellobiose glucosidase activity (GO:0080079), phlorizin hydrolase activity (GO:0140749), catalytic activity (GO:0003824), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of apical plasma membrane (GO:0098591), membrane (GO:0016020), apical plasma membrane (GO:0016324)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Digestion	1
Diseases of carbohydrate metabolism	1
Diseases of metabolism	1
Disease	1
Digestion and absorption	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
disaccharide catabolic process	2
hydrolase activity, hydrolyzing O-glycosyl compounds	2
glycosylceramidase activity	2
lactose metabolic process	1
glycosylceramide metabolic process	1
glycosphingolipid catabolic process	1
ceramide catabolic process	1
flavonoid catabolic process	1
flavone metabolic process	1
cellobiose metabolic process	1
primary metabolic process	1
glucosidase activity	1
identical protein binding	1
protein dimerization activity	1
beta-glucosidase activity	1
molecular_function	1
hydrolase activity, acting on glycosyl bonds	1
catalytic activity	1
hydrolase activity	1
membrane	1
cell periphery	1
external side of plasma membrane	1
apical plasma membrane	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1

Protein interactions and networks

STRING

756 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LCT	GLB1	P16278	901
LCT	SI	P14410	840
LCT	GATA5	Q9BWX5	818
LCT	MCM6	Q14566	798
LCT	HNF1A	P20823	771
LCT	MGAM	O43451	767
LCT	LAT2	Q9GZY6	716
LCT	CDX2	Q99626	635
LCT	SLC5A1	P13866	627
LCT	MGAM2	Q2M2H8	623
LCT	GATA6	P78327	577
LCT	PCBD1	P61457	548
LCT	SLC60A2	Q5TF39	480
LCT	TENM2	Q9NT68	478
LCT	TREH	O43280	458

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SRC	LCT	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (5): LCT (Affinity Capture-MS), CANX (Affinity Capture-Western), HSPA5 (Affinity Capture-Western), LCT (Affinity Capture-MS), PAXIP1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0D3QS97, O02668, O18733, O54728, O70320, O88923, O94910, O95490, O97817, O97827, O97831, P03957, P09848, P0C6R3, P10959, P23613, P23953, P38568, P41245, P48794, P50282, P50757, Q02401, Q05017, Q06HQ7, Q3TTY0, Q3UV74, Q58DX5, Q5EA41, Q5GRG2, Q61627, Q62640, Q62803, Q63880, Q6AW46, Q6NT32, Q6P1J6, Q6Q4G3, Q7SZI7, Q8C129

Diamond homologs: A0AAW1I778, A2SY66, A3BMZ5, A3C053, A3RF67, B3H5Q1, B6ZKM3, B6ZKM4, B6ZKM5, B6ZKN1, B7F7K7, B7F8N7, B8AVF0, B9FHH2, D5MTF8, E3W9M2, E3W9M3, O48779, O64879, O64882, O64883, O65458, O80689, O80690, P09848, P09849, P26204, P26205, P29092, P37702, P49235, Q00326, Q0DA21, Q0DIT2, Q0J0G1, Q0J0G2, Q0J0N4, Q1XH04, Q1XH05, Q1XIR9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDX2	“up-regulates quantity by expression”	LCT	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	14
Uncertain significance	419
Likely benign	398
Benign	63

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073986	NM_002299.4(LCT):c.4967_4976del (p.Asn1656fs)	Pathogenic
1408255	NM_002299.4(LCT):c.5111+1del	Pathogenic
1451518	NM_002299.4(LCT):c.2110_2111insC (p.Asp704fs)	Pathogenic
1453122	NM_002299.4(LCT):c.443_444dup (p.Asp149fs)	Pathogenic
1456272	NM_002299.4(LCT):c.4062C>A (p.Tyr1354Ter)	Pathogenic
1964400	NM_002299.4(LCT):c.386_389dup (p.Leu131fs)	Pathogenic
2020399	NM_002299.4(LCT):c.3458G>A (p.Trp1153Ter)	Pathogenic
2051413	NM_002299.4(LCT):c.553C>T (p.Gln185Ter)	Pathogenic
2065895	NM_002299.4(LCT):c.3166dup (p.Arg1056fs)	Pathogenic
2097185	NM_002299.4(LCT):c.4324del (p.Leu1442fs)	Pathogenic
2104544	NM_002299.4(LCT):c.742_743del (p.Ser247_Leu248insTer)	Pathogenic
2104858	NM_002299.4(LCT):c.391del (p.Leu131fs)	Pathogenic
2812857	NM_002299.4(LCT):c.4935_4936insTGATGAATACGCGG (p.Ile1646Ter)	Pathogenic
2855669	NM_002299.4(LCT):c.2540del (p.Phe847fs)	Pathogenic
2994732	NM_002299.4(LCT):c.27dup (p.Ile10fs)	Pathogenic
3018668	NM_002299.4(LCT):c.3931C>T (p.Arg1311Ter)	Pathogenic
3608962	NM_002299.4(LCT):c.5506C>T (p.Arg1836Ter)	Pathogenic
3618483	NM_002299.4(LCT):c.664C>T (p.Arg222Ter)	Pathogenic
3625419	NM_002299.4(LCT):c.1088G>A (p.Trp363Ter)	Pathogenic
3639526	NM_002299.4(LCT):c.979A>T (p.Lys327Ter)	Pathogenic
3643650	NM_002299.4(LCT):c.2423del (p.Pro808fs)	Pathogenic
3689437	NM_002299.4(LCT):c.2291dup (p.Asn764fs)	Pathogenic
4718981	NM_002299.4(LCT):c.1288del (p.Ser430fs)	Pathogenic
4720430	NM_002299.4(LCT):c.1006_1018dup (p.Leu340fs)	Pathogenic
4734040	NM_002299.4(LCT):c.2281del (p.Glu761fs)	Pathogenic
4750855	NM_002299.4(LCT):c.5359C>T (p.Arg1787Ter)	Pathogenic
4761989	NM_002299.4(LCT):c.4996_4997del (p.Glu1665_Ser1666insTer)	Pathogenic
4768184	NM_002299.4(LCT):c.211_215del (p.Phe71fs)	Pathogenic
4780927	NM_002299.4(LCT):c.762C>A (p.Cys254Ter)	Pathogenic
56387	NM_002299.4(LCT):c.1692_1696del (p.Val565fs)	Pathogenic

SpliceAI

3012 predictions. Top by Δscore:

Variant	Effect	Δscore
2:135794634:GACTT:G	donor_loss	1.0000
2:135794636:CTTAC:C	donor_loss	1.0000
2:135794638:TACC:T	donor_loss	1.0000
2:135794639:A:AC	donor_gain	1.0000
2:135794639:A:C	donor_loss	1.0000
2:135794640:C:CC	donor_gain	1.0000
2:135794640:C:G	donor_loss	1.0000
2:135794640:CCTGT:C	donor_gain	1.0000
2:135798023:CCTT:C	donor_loss	1.0000
2:135798024:CTTA:C	donor_loss	1.0000
2:135798025:TTA:T	donor_loss	1.0000
2:135798027:A:AC	donor_gain	1.0000
2:135798028:C:CC	donor_gain	1.0000
2:135803925:CTTA:C	donor_loss	1.0000
2:135803926:TTACC:T	donor_loss	1.0000
2:135803927:TACCT:T	donor_loss	1.0000
2:135803928:A:C	donor_loss	1.0000
2:135803929:C:CA	donor_loss	1.0000
2:135804129:C:CC	acceptor_gain	1.0000
2:135804763:ATAC:A	donor_loss	1.0000
2:135804764:TAC:T	donor_loss	1.0000
2:135804765:AC:A	donor_loss	1.0000
2:135809989:GATAG:G	acceptor_gain	1.0000
2:135809990:ATAG:A	acceptor_gain	1.0000
2:135809991:TAG:T	acceptor_gain	1.0000
2:135809992:AG:A	acceptor_gain	1.0000
2:135809992:AGC:A	acceptor_loss	1.0000
2:135809994:C:CC	acceptor_gain	1.0000
2:135809996:G:C	acceptor_gain	1.0000
2:135812953:CCAC:C	acceptor_gain	1.0000

AlphaMissense

12758 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:135804874:A:G	W1453R	0.997
2:135804874:A:T	W1453R	0.997
2:135804077:A:G	W1506R	0.996
2:135804077:A:T	W1506R	0.996
2:135809409:A:G	W980R	0.996
2:135809409:A:T	W980R	0.996
2:135789760:A:G	W1792R	0.994
2:135789760:A:T	W1792R	0.994
2:135803996:A:G	W1533R	0.994
2:135803996:A:T	W1533R	0.994
2:135805015:A:G	W1406R	0.994
2:135805015:A:T	W1406R	0.994
2:135807149:A:C	S1384R	0.994
2:135807149:A:T	S1384R	0.994
2:135807151:T:G	S1384R	0.994
2:135809169:A:G	W1060R	0.994
2:135809169:A:T	W1060R	0.994
2:135789734:C:A	W1800C	0.993
2:135789734:C:G	W1800C	0.993
2:135789736:A:G	W1800R	0.993
2:135789736:A:T	W1800R	0.993
2:135794709:A:C	N1681K	0.993
2:135794709:A:T	N1681K	0.993
2:135798126:A:G	W1627R	0.993
2:135798126:A:T	W1627R	0.993
2:135800761:A:G	L1571P	0.993
2:135790747:T:A	E1749V	0.992
2:135800753:C:G	A1574P	0.992
2:135803980:T:A	E1538V	0.992
2:135805013:C:A	W1406C	0.992

dbSNP variants (sampled 300 via entrez): RS1000083928 (2:135824966 T>A,C), RS1000151951 (2:135798880 C>T), RS1000262543 (2:135804257 T>G), RS1000282026 (2:135811753 G>T), RS1000305089 (2:135820481 C>T), RS1000396232 (2:135812128 C>T), RS1000479966 (2:135813649 G>A), RS1000521054 (2:135835302 A>G), RS1000664729 (2:135787871 T>C), RS1000787310 (2:135811349 T>A), RS1000991346 (2:135807728 G>T), RS1001129207 (2:135791185 G>A), RS1001287966 (2:135809892 G>A,C), RS1001292152 (2:135830054 A>G), RS1001396256 (2:135816972 G>A,C)

Disease associations

OMIM: gene MIM:603202 | disease phenotypes: MIM:223000

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital lactase deficiency	Strong	Autosomal recessive

Mondo (1): congenital lactase deficiency (MONDO:0009115)

Orphanet (1): Congenital lactase deficiency (Orphanet:53690)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0002014	Diarrhea
HP:0003623	Neonatal onset
HP:0004789	Lactose intolerance
HP:0025130	Decreased small intestinal mucosa lactase level

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001180_1	Plasma omega-3 polyunsaturated fatty acid levels (alphalinolenic acid)	3.000000e-07
GCST005951_44	Body mass index	1.000000e-09
GCST006585_1124	Blood protein levels	5.000000e-210
GCST009418_1	Lactose tolerance test	3.000000e-06
GCST009733_39	Urinary metabolite levels in chronic kidney disease	9.000000e-18
GCST012202_1	Distal/Left-sided colorectal cancer	3.000000e-08
GCST012205_1	Distal colorectal cancer	8.000000e-06
GCST012496_1	Lung function (FVC)	2.000000e-09
GCST90002393_203	Monocyte count	1.000000e-11
GCST90002398_350	Neutrophil count	1.000000e-15
GCST90002399_111	Neutrophil percentage of white cells	2.000000e-11
GCST90002407_64	White blood cell count	5.000000e-12
GCST90011899_60	Aspartate aminotransferase levels	2.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007759	alpha-linolenic acid measurement
EFO:0004340	body mass index
EFO:0010557	lactose tolerance test
EFO:0005116	urinary metabolite measurement
EFO:0004312	vital capacity
EFO:0005091	monocyte count
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562600	Lactase Deficiency, Congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075131 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 34,265 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL110458	MIGALASTAT	4	430
CHEMBL1561	MIGLITOL	4	29,089
CHEMBL307429	DUVOGLUSTAT	2	4,739
CHEMBL3354637	NIZUBAGLUSTAT	2	7

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 23 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.05	IC50	9000	nM	CHEMBL3354622

PubChem BioAssay actives

1 with measured affinity, of 37 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(1S)-1-(4-phenylphenyl)ethoxy]pentyl]piperidine-3,4,5-triol	1166041: Inhibition of intestinal lactase (unknown origin)	ic50	9.0000	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Lipopolysaccharides	affects response to substance, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Cyclosporine	increases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, decreases expression	1
Palmitic Acid	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1099882	Binding	Inhibition of lactase by HPLC	Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_WY48	MDCK-17	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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