LEMD2

Summary

LEMD2 (LEM domain nuclear envelope protein 2, HGNC:21244) is a protein-coding gene on chromosome 6p21.31, encoding LEM domain-containing protein 2 (Q8NC56). Nuclear lamina-associated inner nuclear membrane protein that is involved in nuclear structure organization, maintenance of nuclear envelope (NE) integrity and NE reformation after mitosis. It is a selective cancer dependency (DepMap: 19.1% of cell lines).

This gene encodes a LEM domain-containing transmembrane protein of the inner nuclear membrane. The protein is involved in nuclear structure organization and plays a role in cell signaling and differentiation. Mutations in this gene result in Cataract 46, juvenile-onset. Multiple transcript variants have been found for this gene.

Source: NCBI Gene 221496 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Marbach-Rustad progeroid syndrome (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 133 total — 1 pathogenic
• Phenotypes (HPO): 37
• Cancer dependency (DepMap): dependent in 19.1% of screened cell lines
• MANE Select transcript: NM_181336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21244
Approved symbol	LEMD2
Name	LEM domain nuclear envelope protein 2
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Aliases	dJ482C21.1, NET25, LEM2
Ensembl gene	ENSG00000161904
Ensembl biotype	protein_coding
OMIM	616312
Entrez	221496

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000293760, ENST00000421671, ENST00000442696, ENST00000502643, ENST00000504692, ENST00000506578, ENST00000508327, ENST00000510598, ENST00000511171, ENST00000512368, ENST00000513701, ENST00000513832, ENST00000514636, ENST00000924030, ENST00000967487, ENST00000967488, ENST00000967489

RefSeq mRNA: 4 — MANE Select: NM_181336 NM_001143944, NM_001348709, NM_001348710, NM_181336

CCDS: CCDS47411, CCDS4785

Canonical transcript exons

ENST00000293760 — 9 exons

Exon	Start	End
ENSE00002064493	33771213	33772778
ENSE00002080246	33788381	33789130
ENSE00003458282	33780100	33780179
ENSE00003514801	33786734	33786774
ENSE00003577503	33778242	33778387
ENSE00003637494	33777138	33777239
ENSE00003646222	33784352	33784427
ENSE00003658800	33781077	33781153
ENSE00003660985	33776954	33777056

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 97.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6024 / max 305.0902, expressed in 1791 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73191	13.9821	1788
73190	0.3611	167
73185	0.1643	25
73187	0.0499	15
73186	0.0292	6
73188	0.0101	1
73189	0.0057	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.30	gold quality
cerebellar hemisphere	UBERON:0002245	97.17	gold quality
cerebellar cortex	UBERON:0002129	96.98	gold quality
lower esophagus mucosa	UBERON:0035834	96.36	gold quality
mucosa of stomach	UBERON:0001199	96.21	gold quality
right uterine tube	UBERON:0001302	96.20	gold quality
right lobe of thyroid gland	UBERON:0001119	96.18	gold quality
granulocyte	CL:0000094	96.14	gold quality
endocervix	UBERON:0000458	96.11	gold quality
left lobe of thyroid gland	UBERON:0001120	96.08	gold quality
body of uterus	UBERON:0009853	96.00	gold quality
adenohypophysis	UBERON:0002196	95.99	gold quality
metanephros cortex	UBERON:0010533	95.99	gold quality
left ovary	UBERON:0002119	95.93	gold quality
right ovary	UBERON:0002118	95.83	gold quality
skin of leg	UBERON:0001511	95.81	gold quality
body of pancreas	UBERON:0001150	95.64	gold quality
peripheral nervous system	UBERON:0000010	95.52	gold quality
nerve	UBERON:0001021	95.52	gold quality
tibial nerve	UBERON:0001323	95.52	gold quality
right lung	UBERON:0002167	95.50	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.50	gold quality
ectocervix	UBERON:0012249	95.40	gold quality
lower esophagus	UBERON:0013473	95.39	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.39	gold quality
skin of abdomen	UBERON:0001416	95.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.27	gold quality
upper lobe of left lung	UBERON:0008952	95.05	gold quality
mucosa of transverse colon	UBERON:0004991	95.04	gold quality
transverse colon	UBERON:0001157	95.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting LEMD2, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-3652	97.71	65.43	1890

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• We conclude that Lem2p/LEM2 is a conserved nuclear site-specific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope. (PMID:28242692)
• a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome (PMID:30905398)
• LEMD2 is required for recruitment of the ESCRT-III membrane repair machinery to ruptures; however, neither LEMD2 nor ESCRT-III is required to repair ruptures. These results reveal a new role for BAF in the response to and repair of nuclear ruptures. (PMID:31147383)
• Comparative Interactome Analysis of Emerin, MAN1 and LEM2 Reveals a Unique Role for LEM2 in Nucleotide Excision Repair. (PMID:32085595)
• Regulated lipid synthesis and LEM2/CHMP7 jointly control nuclear envelope closure. (PMID:32271860)
• LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation (PMID:32494070)
• SATB2-LEMD2 interaction links nuclear shape plasticity to regulation of cognition-related genes. (PMID:33319920)
• Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy. (PMID:36377660)
• The Role of the LEMD2 p.L13R Mutation in Dilated Cardiomyopathy. (PMID:36656966)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lemd2	ENSMUSG00000044857
rattus_norvegicus	Lemd2	ENSRNOG00000025864
drosophila_melanogaster	MAN1	FBGN0034962
caenorhabditis_elegans		WBGENE00002275

Paralogs (2): ANKLE1 (ENSG00000160117), LEMD3 (ENSG00000174106)

Protein

Protein identifiers

LEM domain-containing protein 2 — Q8NC56 (reviewed: Q8NC56)

All UniProt accessions (6): D6R958, D6RBV0, Q8NC56, H0Y8H8, H0Y9B7, H7C2Z0

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear lamina-associated inner nuclear membrane protein that is involved in nuclear structure organization, maintenance of nuclear envelope (NE) integrity and NE reformation after mitosis. Plays a role as transmembrane adapter for the endosomal sorting complexes required for transport (ESCRT), and is thereby involved in ESCRT-mediated NE reformation. Promotes ESCRT-mediated NE closure by recruiting CHMP7 and downstream ESCRT-III proteins IST1/CHMP8 and CHMP2A to the reforming NE during anaphase. During nuclear reassembly, condenses into a liquid-like coating around microtubule spindles and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin, and the spindle to facilitate early nuclear sealing. Plays a role in the organization of heterochromatin associated with the NE and in the maintenance of NE organization under mechanical stress. Required for embryonic development and involved in regulation of several signaling pathways such as MAPK and AKT. Required for myoblast differentiation involving regulation of ERK signaling. Essential for cardiac homeostasis and proper heart function.

Subunit / interactions. Interacts (via N-terminus) with LMNA isoform C (via C-terminus) (in vitro). Interacts (via LEM domain) with BANF1. Interacts (via C-terminus) with CHMP7. Interacts (via N-terminus) with tubulin; the interaction causes microtubule bundling and stabilization (in vitro).

Subcellular location. Nucleus inner membrane. Nucleus envelope. Cytoplasm. Cytoskeleton. Spindle.

Tissue specificity. Ubiquitously expressed, including bone marrow, brain, kidney, colon, skeletal muscle, thymus, testis and uterus.

Post-translational modifications. Phosphorylated; strongly phosphorylated in mitosis compared to G1/S.

Disease relevance. Cataract 46, juvenile-onset, with or without arrhythmic cardiomyopathy (CTRCT46) [MIM:212500] A form of cataract, an opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. CTRCT46 can be associated with variable onset of a severe form of arrhythmic cardiomyopathy resulting in sudden cardiac death. The disease is caused by variants affecting the gene represented in this entry. Marbach-Rustad progeroid syndrome (MARUPS) [MIM:619322] An autosomal dominant syndrome characterized by progeria-like appearance with little subcutaneous fat and triangular facies, growth retardation, short stature, hypoplastic mandible crowded with unerupted supernumerary teeth, and cerebellar intention tremor. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The LEM domain is required for inner nuclear membrane (INM) localization and contains a BANF1 conserved binding motif which allows localization to chromatin. In late anaphase, as the reforming nuclear envelope (NE) surrounds the chromatin disk, both the LEM domain and the disordered regions are necessary for localization to the NE core. The disordered regions, also named low complexity domain, confer the ability to phase separate. In late anaphase, as the reforming nuclear envelope (NE) surrounds the chromatin disk, both the LEM domain and the disordered regions are necessary for localization to the NE core. During NE reformation, the proline-arginine-rich sequence within the disordered region binds microtubules, targeting LEM2 condensation to spindle microtubules traversing the nascent NE. The winged-helix (WH) region (residues 395-503) activates the ESCRT-II/ESCRT-III hybrid protein CHMP7 to form co-oligomeric rings around spindle microtubules to facilitate early nuclear sealing.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NC56-1	1	yes
Q8NC56-2	2

RefSeq proteins (4): NP_001137416, NP_001335638, NP_001335639, NP_851853* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003887	LEM_dom	Domain
IPR011015	LEM/LEM-like_dom_sf	Homologous_superfamily
IPR018996	Man1/Src1-like_C	Domain
IPR041885	MAN1_winged_helix_dom	Homologous_superfamily
IPR052277	INM_ESCRT-Associated	Family

Pfam: PF03020, PF09402

UniProt features (27 total): modified residue 6, region of interest 5, mutagenesis site 4, compositionally biased region 3, transmembrane region 2, sequence variant 2, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NC56-F1	71.49	0.17

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 (6): 2, 166, 175, 497, 499, 501

Mutagenesis-validated functional residues (4):

Position	Phenotype
21–24	disrupts lemd2 accumulation within the nuclear envelope (ne) and subsequent ne core enrichment in anaphase cells.
43–202	compromises nuclear envelope enrichment.
145–213	failure to enrich at microtubule-containing nuclear envelope core during anaphase.
415–485	does not affect nuclear envelope enrichment.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-2980766	Nuclear Envelope Breakdown
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-4419969	Depolymerization of the Nuclear Lamina
R-HSA-9668328	Sealing of the nuclear envelope (NE) by ESCRT-III
R-HSA-1640170	Cell Cycle
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-2995410	Nuclear Envelope (NE) Reassembly
R-HSA-68875	Mitotic Prophase
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic

MSigDB gene sets: 229 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, PAX4_01, GOBP_NEUROGENESIS, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, CEBPB_01, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GTGCCTT_MIR506, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_HEART_MORPHOGENESIS, GOBP_NUCLEUS_ORGANIZATION, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION

GO Biological Process (8): nuclear envelope organization (GO:0006998), neurogenesis (GO:0022008), skeletal muscle cell differentiation (GO:0035914), negative regulation of MAPK cascade (GO:0043409), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), heart formation (GO:0060914), protein localization to chromatin (GO:0071168), nuclear membrane organization (GO:0071763)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (11): chromatin (GO:0000785), nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), spindle (GO:0005819), membrane (GO:0016020), nuclear membrane (GO:0031965), nuclear periphery (GO:0034399), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Nuclear Envelope (NE) Reassembly	2
M Phase	2
Mitotic Prophase	1
Nuclear Envelope Breakdown	1
Mitotic Anaphase	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
membrane organization	2
cell differentiation	2
negative regulation of intracellular signal transduction	2
nucleus	2
endomembrane system	2
intracellular membraneless organelle	2
intracellular membrane-bounded organelle	2
nucleus organization	1
endomembrane system organization	1
nervous system development	1
skeletal muscle tissue development	1
MAPK cascade	1
regulation of MAPK cascade	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
heart morphogenesis	1
animal organ formation	1
protein localization to chromosome	1
nuclear envelope organization	1
binding	1
chromosome	1
organelle envelope	1
organelle inner membrane	1
nuclear membrane	1
microtubule cytoskeleton	1
nuclear envelope	1
organelle membrane	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2043 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEMD2	CHMP7	Q8WUX9	966
LEMD2	BANF2	Q9H503	848
LEMD2	EMD	P50402	834
LEMD2	BANF1	O75531	809
LEMD2	ANKLE2	Q86XL3	669
LEMD2	ANKLE1	Q8NAG6	626
LEMD2	LBR	Q14739	575
LEMD2	PLPP7	Q8NBV4	572
LEMD2	DNAJC24	Q6P3W2	548
LEMD2	SUN1	O94901	531
LEMD2	IST1	P53990	505
LEMD2	CIMAP2	Q3ZCV2	484
LEMD2	LMNB1	P20700	483
LEMD2	SUN2	Q9UH99	481
LEMD2	TMPO	P08918	479

IntAct

135 interactions, top by confidence:

A	B	Type	Score
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
SGSM3	LEMD2	psi-mi:“MI:0915”(physical association)	0.590
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
GDPD5	GOLIM4	psi-mi:“MI:0914”(association)	0.530
KCNA10	GAPDHS	psi-mi:“MI:0914”(association)	0.530
ANO6	CDC27	psi-mi:“MI:0914”(association)	0.530
CHRNB3	TYRO3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
CSGALNACT2	TPST1	psi-mi:“MI:0914”(association)	0.530
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530

BioGRID (162): LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS)

ESM2 similar proteins: A1Z623, A2SXS5, A8YXY3, F1LQY6, O02718, O19011, O60613, P01137, P04202, P07200, P09533, P11456, P18341, P50747, P54831, Q08BI9, Q0P5I0, Q1LZ96, Q2KIJ6, Q2TBX5, Q38HS2, Q3UHE1, Q3UX43, Q58CS8, Q5C9Z4, Q5R812, Q5RB75, Q6IEE6, Q6PCX7, Q6X4M2, Q802F3, Q802G7, Q8BJQ9, Q8IVD9, Q8NC56, Q8R1N4, Q8R1T1, Q8TDX6, Q8VHC3, Q8WUX9

Diamond homologs: Q6DVA0, Q8NC56, Q9WU40, Q9XTB5, Q9Y2U8, O13845, P42166, P42167, Q14498, Q5RC80, Q61029, Q61033, Q62733, Q8VH51, O01971, Q7JRE4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
R-HSA-425366	6	9.5×	2e-03
Ion homeostasis	5	8.9×	7e-03
Potassium Channels	6	7.1×	7e-03
Neurotransmitter receptors and postsynaptic signal transmission	8	7.0×	1e-03
Cardiac conduction	7	6.7×	3e-03
Transmission across Chemical Synapses	9	6.0×	1e-03
Neuronal System	15	5.8×	1e-05
SLC-mediated transmembrane transport	11	5.7×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
synaptic transmission, cholinergic	6	33.0×	5e-06
acetylcholine receptor signaling pathway	6	25.6×	2e-05
zinc ion transmembrane transport	5	24.1×	2e-04
membrane depolarization	6	21.0×	7e-05
neuromuscular synaptic transmission	5	20.6×	4e-04
intracellular zinc ion homeostasis	6	19.8×	8e-05
monoatomic ion transmembrane transport	12	17.1×	6e-09
action potential	5	12.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	77
Likely benign	16
Benign	25

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
235192	NM_181336.4(LEMD2):c.38T>G (p.Leu13Arg)	Pathogenic

SpliceAI

1300 predictions. Top by Δscore:

Variant	Effect	Δscore
6:33772661:AGT:A	donor_gain	1.0000
6:33776948:ACTCA:A	donor_loss	1.0000
6:33776951:C:CC	donor_loss	1.0000
6:33776952:A:AC	donor_gain	1.0000
6:33776953:C:CC	donor_gain	1.0000
6:33776953:CC:C	donor_loss	1.0000
6:33776953:CCGG:C	donor_gain	1.0000
6:33777052:CACGT:C	acceptor_gain	1.0000
6:33777053:ACGT:A	acceptor_gain	1.0000
6:33777054:CGT:C	acceptor_gain	1.0000
6:33777054:CGTC:C	acceptor_gain	1.0000
6:33777055:GT:G	acceptor_gain	1.0000
6:33777056:TCT:T	acceptor_loss	1.0000
6:33777057:C:CC	acceptor_gain	1.0000
6:33777058:T:G	acceptor_loss	1.0000
6:33778235:GACTT:G	donor_loss	1.0000
6:33778236:ACTT:A	donor_loss	1.0000
6:33778237:CTTA:C	donor_loss	1.0000
6:33778238:TTACA:T	donor_loss	1.0000
6:33778239:TACA:T	donor_loss	1.0000
6:33778240:A:AC	donor_gain	1.0000
6:33778240:AC:A	donor_loss	1.0000
6:33778240:ACAC:A	donor_gain	1.0000
6:33778241:C:CA	donor_gain	1.0000
6:33778241:CA:C	donor_gain	1.0000
6:33778241:CACC:C	donor_gain	1.0000
6:33778241:CACCA:C	donor_gain	1.0000
6:33778383:TCAAC:T	acceptor_gain	1.0000
6:33778384:CAACC:C	acceptor_gain	1.0000
6:33778386:ACCTG:A	acceptor_loss	1.0000

AlphaMissense

3200 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:33772664:C:A	W492C	1.000
6:33772664:C:G	W492C	1.000
6:33772665:C:G	W492S	1.000
6:33772666:A:G	W492R	1.000
6:33772666:A:T	W492R	1.000
6:33772670:C:A	W490C	1.000
6:33772670:C:G	W490C	1.000
6:33772672:A:G	W490R	1.000
6:33772672:A:T	W490R	1.000
6:33772716:A:C	I475S	1.000
6:33772716:A:G	I475T	1.000
6:33772716:A:T	I475N	1.000
6:33772739:G:C	F467L	1.000
6:33772739:G:T	F467L	1.000
6:33772740:A:C	F467C	1.000
6:33772740:A:G	F467S	1.000
6:33772741:A:G	F467L	1.000
6:33772749:G:T	A464D	1.000
6:33772750:C:G	A464P	1.000
6:33772757:C:A	W461C	1.000
6:33772757:C:G	W461C	1.000
6:33772758:C:G	W461S	1.000
6:33772759:A:G	W461R	1.000
6:33772759:A:T	W461R	1.000
6:33776969:A:T	I449N	1.000
6:33776978:T:A	D446V	1.000
6:33776978:T:G	D446A	1.000
6:33776979:C:G	D446H	1.000
6:33776982:G:T	R445S	1.000
6:33777050:A:T	V422D	1.000

dbSNP variants (sampled 300 via entrez): RS1000081712 (6:33790004 A>G), RS1000306701 (6:33776081 G>A), RS1000325346 (6:33779767 C>T), RS1000409331 (6:33781268 C>A,T), RS1000577775 (6:33789593 G>T), RS1000663623 (6:33784357 T>C,G), RS1000676973 (6:33775876 A>G), RS1000984745 (6:33778420 G>C), RS1001115337 (6:33771382 G>A,C,T), RS1001143148 (6:33772448 C>A,T), RS1001145099 (6:33771588 C>T), RS1001204902 (6:33779034 G>A), RS1001264295 (6:33784988 A>T), RS1001432959 (6:33775581 C>T), RS1001465477 (6:33775838 A>C,G)

Disease associations

OMIM: gene MIM:616312 | disease phenotypes: MIM:212500, MIM:187100, MIM:619322

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 46 juvenile-onset	Strong	Autosomal recessive
Marbach-Rustad progeroid syndrome	Strong	Autosomal dominant
early-onset posterior subcapsular cataract	Supportive	Autosomal dominant
total early-onset cataract	Supportive	Autosomal dominant

Mondo (7): cataract 46 juvenile-onset (MONDO:0008925), microcephaly (MONDO:0001149), exophthalmos (MONDO:0004770), teeth, supernumerary (MONDO:0008533), Marbach-Rustad progeroid syndrome (MONDO:0859147), early-onset posterior subcapsular cataract (MONDO:0018610), total early-onset cataract (MONDO:0021548)

Orphanet (3): Early onset non-syndromic cataract (Orphanet:91492), Wormian bones-micrognathia-abnormal dentition-progeroid syndrome (Orphanet:659873), OBSOLETE: Cataract, Hutterite type (Orphanet:98987)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000252	Microcephaly
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000444	Convex nasal ridge
HP:0000520	Proptosis
HP:0000586	Shallow orbits
HP:0000668	Hypodontia
HP:0000680	Delayed eruption of primary teeth
HP:0000706	Eruption failure
HP:0000855	Insulin resistance
HP:0000894	Short clavicles
HP:0001015	Prominent superficial veins
HP:0001118	Juvenile cataract
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001645	Sudden cardiac death
HP:0001788	Premature rupture of membranes
HP:0002003	Large forehead
HP:0002080	Intention tremor
HP:0002645	Wormian bones
HP:0003429	CNS hypomyelination
HP:0003758	Reduced subcutaneous adipose tissue
HP:0004322	Short stature
HP:0004349	Reduced bone mineral density
HP:0004396	Poor appetite

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000703_3	Phosphorus levels	1.000000e-11
GCST001280_9	Alzheimer’s disease (age of onset)	7.000000e-06
GCST001762_714	Obesity-related traits	8.000000e-06
GCST002094_5	Crohn’s disease	1.000000e-08
GCST002783_243	Body mass index	9.000000e-06
GCST002783_422	Body mass index	8.000000e-06
GCST004557_220	Body mass index	3.000000e-08
GCST004558_63	Body mass index (joint analysis main effects and physical activity interaction)	7.000000e-06
GCST004558_90	Body mass index (joint analysis main effects and physical activity interaction)	8.000000e-08
GCST006920_1	Regular attendance at a gym or sports club	4.000000e-08
GCST007201_422	Schizophrenia	2.000000e-08
GCST007656_5	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	3.000000e-15
GCST008919_7	Asthma and attention deficit hyperactivity disorder	4.000000e-08
GCST009391_1215	Metabolite levels	5.000000e-06
GCST009391_1223	Metabolite levels	6.000000e-06
GCST009391_133	Metabolite levels	5.000000e-06
GCST009391_1450	Metabolite levels	2.000000e-06
GCST009391_1495	Metabolite levels	5.000000e-06
GCST009391_1514	Metabolite levels	5.000000e-06
GCST009391_1870	Metabolite levels	9.000000e-07
GCST009391_1879	Metabolite levels	2.000000e-06
GCST009391_313	Metabolite levels	6.000000e-06
GCST010241_235	Apolipoprotein A1 levels	2.000000e-09
GCST012332_74	Multisite chronic pain	2.000000e-08
GCST012333_1	Multisite chronic pain	2.000000e-08

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0004861	phosphorus measurement
EFO:0004847	age at onset
EFO:0003939	energy intake
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0009592	social interaction measurement
EFO:0010420	triacylglycerol 54:2 measurement
EFO:0010421	triacylglycerol 54:3 measurement
EFO:0010355	diacylglycerol 36:2 measurement
EFO:0010410	triacylglycerol 50:3 measurement
EFO:0010416	triacylglycerol 52:4 measurement
EFO:0010417	triacylglycerol 52:5 measurement
EFO:0010411	triacylglycerol 50:4 measurement
EFO:0010414	triacylglycerol 52:2 measurement
EFO:0010430	triacylglycerol 56:3 measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0010100	multisite chronic pain

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D005094	Exophthalmos	C11.675.349
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D014096	Tooth, Supernumerary	C07.650.800.850; C07.793.700.850; C16.131.850.800.850
C538286	Cataract Hutterite type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
coumarin	increases phosphorylation	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Clozapine	affects cotreatment, increases expression	1
Copper	increases expression, affects binding	1
Cuprizone	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Disulfiram	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Mitoxantrone	affects response to substance	1
Phthalic Acids	increases methylation	1
Potassium Dichromate	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Urethane	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01204359	PHASE3	UNKNOWN	The Prospective Study of Standard Treatment of Graves Disease Iodine 131 and Prevention of Adverse Reactions
NCT06226545	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of LASN01 in Patients With Thyroid Eye Disease
NCT06068348	Not specified	ACTIVE_NOT_RECRUITING	Liquid Biopsy Collection Study
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.
NCT05276063	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Phase 2b, Study of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)
NCT06112340	PHASE2/PHASE3	RECRUITING	Extension Study of Two Doses of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)
NCT04025034	Not specified	COMPLETED	Deep Lateral Wall Partial Rim-Sparing Orbital Decompression for Treatment of Thyroid-Related Orbitopathy
NCT04704414	Not specified	UNKNOWN	Exophthalmometry With 3D Face Scanners