MCFD2

Summary

MCFD2 (multiple coagulation factor deficiency 2, ER cargo receptor complex subunit, HGNC:18451) is a protein-coding gene on chromosome 2p21, encoding Multiple coagulation factor deficiency protein 2 (Q8NI22). The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.

This gene encodes a soluble luminal protein with two calmodulin-like EF-hand motifs at its C-terminus. This protein forms a complex with LMAN1 (lectin mannose binding protein 1; also known as ERGIC-53) that facilitates the transport of coagulation factors V (FV) and VIII (FVIII) from the endoplasmic reticulum to the Golgi apparatus via an endoplasmic reticulum Golgi intermediate compartment (ERGIC). Mutations in this gene cause combined deficiency of FV and FVIII (F5F8D); a rare autosomal recessive bleeding disorder characterized by mild to moderate bleeding and coordinate reduction in plasma FV and FVIII levels. This protein has also been shown to maintain stem cell potential in adult central nervous system and is a marker for testicular germ cell tumors. The 3’ UTR of this gene contains a transposon-like human repeat element named ‘THE 1’. A processed RNA pseudogene of this gene is on chromosome 6p22.1. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 90411 — RefSeq curated summary.

At a glance

• Gene–disease (curated): factor 5 and Factor VIII, combined deficiency of, 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 250 total — 11 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 20
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_139279

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18451
Approved symbol	MCFD2
Name	multiple coagulation factor deficiency 2, ER cargo receptor complex subunit
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	F5F8D, LMAN1IP, SDNSF
Ensembl gene	ENSG00000180398
Ensembl biotype	protein_coding
OMIM	607788
Entrez	90411

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 22 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000319466, ENST00000409105, ENST00000409147, ENST00000409207, ENST00000409218, ENST00000409800, ENST00000409913, ENST00000409973, ENST00000412438, ENST00000417180, ENST00000434262, ENST00000444761, ENST00000470873, ENST00000477791, ENST00000479225, ENST00000487121, ENST00000493804, ENST00000649435, ENST00000895741, ENST00000895742, ENST00000895743, ENST00000895744, ENST00000954307, ENST00000954308, ENST00000954309, ENST00000954310, ENST00000954311

RefSeq mRNA: 7 — MANE Select: NM_139279 NM_001171506, NM_001171507, NM_001171508, NM_001171509, NM_001171510, NM_001171511, NM_139279

CCDS: CCDS33192, CCDS54354, CCDS54355

Canonical transcript exons

ENST00000319466 — 4 exons

Exon	Start	End
ENSE00001580600	46901874	46905594
ENSE00001853841	46915723	46915806
ENSE00003462240	46907810	46907969
ENSE00003674533	46909023	46909177

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.5484 / max 612.4097, expressed in 1823 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28198	41.7793	1819
28201	4.7392	1609
28199	1.4699	964
28204	0.6555	190
28202	0.4537	237
28200	0.4060	228
28203	0.0448	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	99.20	gold quality
seminal vesicle	UBERON:0000998	98.81	gold quality
adrenal tissue	UBERON:0018303	98.69	gold quality
pericardium	UBERON:0002407	98.43	gold quality
stromal cell of endometrium	CL:0002255	98.26	gold quality
left adrenal gland	UBERON:0001234	98.12	gold quality
adrenal gland	UBERON:0002369	98.10	gold quality
adrenal cortex	UBERON:0001235	98.06	gold quality
right adrenal gland	UBERON:0001233	98.03	gold quality
right adrenal gland cortex	UBERON:0035827	97.99	gold quality
left adrenal gland cortex	UBERON:0035825	97.94	gold quality
body of pancreas	UBERON:0001150	97.83	gold quality
germinal epithelium of ovary	UBERON:0001304	97.67	gold quality
pigmented layer of retina	UBERON:0001782	97.64	gold quality
superficial temporal artery	UBERON:0001614	97.63	gold quality
substantia nigra pars compacta	UBERON:0001965	97.46	gold quality
calcaneal tendon	UBERON:0003701	97.34	gold quality
choroid plexus epithelium	UBERON:0003911	97.30	gold quality
synovial joint	UBERON:0002217	97.26	gold quality
blood vessel layer	UBERON:0004797	97.18	gold quality
pancreas	UBERON:0001264	97.16	gold quality
mammary duct	UBERON:0001765	97.16	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.13	gold quality
decidua	UBERON:0002450	97.09	gold quality
cardia of stomach	UBERON:0001162	97.04	gold quality
renal medulla	UBERON:0000362	97.00	gold quality
superior vestibular nucleus	UBERON:0007227	96.98	gold quality
urethra	UBERON:0000057	96.97	gold quality
placenta	UBERON:0001987	96.87	gold quality
parietal pleura	UBERON:0002400	96.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

154 targeting MCFD2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3119	99.92	71.34	2390

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 23)

• inactivating mutations in MCFD2 cause combined deficiency of factor V and factor VIII with a phenotype indistinguishable from that caused by mutations in LMAN1 (PMID:12717434)
• ERGIC-53 and MCFD2 have important functions during cellular response to stress conditions (PMID:15292203)
• LMAN1 and MCFD2 form a cargo receptor complex and the primary sorting signals residing in the B domain direct the binding of factor VIII (PMID:15886209)
• Mutations in (LMAN1) and (MCFD2), have been found to be responsible for the dual deficiency of FV and FVIII. (PMID:16044454)
• Results indicate that ERGIC-53 can bind cargo glycoproteins in an MCFD2-independent fashion and suggest that MCFD2 is a recruitment factor for blood coagulation factors V and VIII. (PMID:17010120)
• phenotype & genotype analyses in 9 Indian patients with combined FV & FVIII deficiency; 2 MCFD2 gene mutations, c.149 + 5G > A splice defect & the p.E71fs accounted for >77% of patients screened; data suggest multiple hotspots of mutations in MCFD2 gene (PMID:17610559)
• The newly identified neuronal stem cell factor, MCFD2 (SDNSF), were expressed in seminoma cells and they were only present in gonocytes up to the second trimester. (PMID:17785371)
• Binding of ERGIC-53 to sugar is enhanced by its interaction with MCFD2, and defects in this interaction in factor V and VIII deeficient patients may be the cause for reduced secretion of factors V and VIII. (PMID:18056485)
• MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2 (PMID:18391077)
• These results provide an explanation for the previously observed calcium dependence of the MCFD2-ERGIC-53 interaction. (PMID:18590741)
• 2 related patients were homozygous for a new missense mutation in the 2d elongation factor hand domain. Tyr135Asn is the 3d missense mutation found in the MCFD2 gene. It may disrupt the MCFD2-LMAN1 interaction. (PMID:18685427)
• The study reports for the first time a case of Combined factor V and factor VIII deficiency disorder in a Tunisian family, resulting from two novel mutations in exon 3 of the MCFD2 gene. (PMID:20004600)
• Data show that mutations in MCFD2 that disrupt the tertiary structure and abolish LMAN1 binding still retain the FV/FVIII binding activities, suggesting that this interaction is independent of Ca(2+)-induced folding of the protein. (PMID:20007547)
• Data present the crystal structure of the LMAN1/MCFD2 complex and relate it to patient mutations. Circular dichroism data show that the majority of the substitution mutations give rise to a disordered or severely destabilized MCFD2 protein. (PMID:20138881)
• We present the identification of a novel MCFD2 gene missense mutation by direct sequencing. (PMID:22535353)
• Mutations in MCFD2 lead to F5F8D (combined deficiency of factor V And factor VIII) due to alterations in MCFD2-LMAN1 complex of coat protein (COP)II complex trafficking machinery; 30% of F5F8D patients have mutations in MCFD2. [REVIEW] (PMID:22764119)
• Results indicate the biological roles of MCFD2 in both vertebrates and invertebrates. (PMID:23660967)
• Data indicate that together with its soluble coreceptor MCFD2, LMAN1 transports coagulation factors V (FV) and VIII (FVIII). (PMID:23709226)
• Studies indicate that the LMAN1-CRD contains distinct, separable binding sites for both its partner protein MCFD2 and the cargo proteins FV/FVIII. (PMID:23852824)
• A novel missense mutation, namely Asp81Ala in exon 3 of MCFD2 gene, is firstly reported and described as a cause of combined FV and FVIII deficiency in a Chinese family. (PMID:25354775)
• Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2 (PMID:29082580)
• that Multiple coagulation factor deficiency protein 2 promotes cancer metastasis by regulating lectin mannose binding 1 and level of galactoside-binding soluble 3 binding protein expression levels (PMID:29679592)
• LMAN1-MCFD2 complex is a cargo receptor for the ER-Golgi transport of alpha1-antitrypsin. (PMID:35322856)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcfd2	ENSDARG00000039757
mus_musculus	Mcfd2	ENSMUSG00000024150
rattus_norvegicus	Mcfd2	ENSRNOG00000015059
drosophila_melanogaster	CG12817	FBGN0037798

Paralogs (1): CGREF1 (ENSG00000138028)

Protein

Protein identifiers

Multiple coagulation factor deficiency protein 2 — Q8NI22 (reviewed: Q8NI22)

Alternative names: Neural stem cell-derived neuronal survival protein

All UniProt accessions (4): Q8NI22, A0A3B3IU18, C9JTR4, H7BZ18

UniProt curated annotations — full annotation on UniProt →

Function. The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins. Plays a role in the secretion of coagulation factors.

Subunit / interactions. Interacts in a calcium-dependent manner with LMAN1.

Subcellular location. Endoplasmic reticulum-Golgi intermediate compartment. Endoplasmic reticulum. Golgi apparatus.

Disease relevance. Factor V and factor VIII combined deficiency 2 (F5F8D2) [MIM:613625] A blood coagulation disorder characterized by bleeding symptoms similar to those in hemophilia or parahemophilia, that are caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma levels of coagulation factors V and VIII are in the range of 5 to 30% of normal. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Essentially unstructured in the absence of calcium ions. Requires calcium ions for folding.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NI22-1	1	yes
Q8NI22-2	2
Q8NI22-3	3

RefSeq proteins (7): NP_001164977, NP_001164978, NP_001164979, NP_001164980, NP_001164981, NP_001164982, NP_644808* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR052110	MCFD2-like	Family

Pfam: PF13499

UniProt features (30 total): binding site 9, helix 6, sequence variant 4, strand 3, splice variant 2, domain 2, signal peptide 1, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
4YGB	X-RAY DIFFRACTION	1.6
3WHT	X-RAY DIFFRACTION	1.8
3A4U	X-RAY DIFFRACTION	1.84
4YGC	X-RAY DIFFRACTION	2.4
3LCP	X-RAY DIFFRACTION	2.45
4YGD	X-RAY DIFFRACTION	2.51
8JP4	ELECTRON MICROSCOPY	2.53
8JP5	ELECTRON MICROSCOPY	2.59
3WHU	X-RAY DIFFRACTION	2.6
3WNX	X-RAY DIFFRACTION	2.75
4YGE	X-RAY DIFFRACTION	3.05
8JP6	ELECTRON MICROSCOPY	3.29
8JP9	ELECTRON MICROSCOPY	3.37
8JP8	ELECTRON MICROSCOPY	3.39
8JP7	ELECTRON MICROSCOPY	3.51
8JPG	ELECTRON MICROSCOPY	6.76
2VRG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NI22-F1	76.97	0.38

Functional residue map

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

Ligand- & substrate-binding residues (9): 133; 135; 140; 81; 83; 85; 92; 129; 131

Post-translational modifications (1): 106

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-5694530	Cargo concentration in the ER
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 267 (showing top): ZHAN_LATE_DIFFERENTIATION_GENES_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_HDAC2, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOCC_COATED_VESICLE, MORF_RFC4, MORF_PRKDC, ATTCTTT_MIR186, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, SCHLOSSER_SERUM_RESPONSE_DN, SANSOM_APC_TARGETS_DN, TAATGTG_MIR323, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (3): gene expression (GO:0010467), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), ER to Golgi transport vesicle membrane (GO:0012507), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), endoplasmic reticulum (GO:0005783), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	2
Asparagine N-linked glycosylation	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
intracellular membrane-bounded organelle	3
transport	2
endomembrane system	2
macromolecule biosynthetic process	1
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
metal ion binding	1
binding	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
COPII-coated ER to Golgi transport vesicle	1
transport vesicle membrane	1
coated vesicle membrane	1
endoplasmic reticulum-Golgi intermediate compartment	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

728 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCFD2	LMAN1	P49257	999
MCFD2	F8	P00451	943
MCFD2	LMAN2L	Q9H0V9	772
MCFD2	LMAN2	Q12907	768
MCFD2	F5	P12259	665
MCFD2	F7	P08709	609
MCFD2	CANX	P27824	584
MCFD2	SURF4	O15260	583
MCFD2	MBL2	P11226	576
MCFD2	LMAN1L	Q9HAT1	575
MCFD2	CALR	P27797	573
MCFD2	CALML4	Q96GE6	550
MCFD2	C3orf18	Q9UK00	458
MCFD2	CTSZ	Q9UBR2	452
MCFD2	MRPL45	Q9BRJ2	439

IntAct

65 interactions, top by confidence:

A	B	Type	Score
LMAN1	MCFD2	psi-mi:“MI:0407”(direct interaction)	0.960
LMAN1	MCFD2	psi-mi:“MI:0915”(physical association)	0.960
MCFD2	LMAN1	psi-mi:“MI:0915”(physical association)	0.960
MCFD2	LMAN1	psi-mi:“MI:0407”(direct interaction)	0.960
SEC13	SEC16A	psi-mi:“MI:0914”(association)	0.640
SLC35A1	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
P2RY6	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
SYS1	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
MCFD2	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
SCD	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
IL1RL1	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
PNLIPRP1	MCFD2	psi-mi:“MI:0915”(physical association)	0.560
MCFD2	CCK	psi-mi:“MI:0915”(physical association)	0.560
MCFD2	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
MCFD2	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (88): AGL (Co-fractionation), CAPZB (Co-fractionation), EIF6 (Co-fractionation), ENOPH1 (Co-fractionation), LARS (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation), MCFD2 (Co-fractionation)

ESM2 similar proteins: A4IG32, B1H2N3, B5X186, B5X4E0, D2HZB0, I6L9G5, J3S9D9, O35783, O35887, O43852, O93390, O93434, P06813, P07090, P07214, P09486, P13213, P16975, P20112, P22676, P47728, Q05186, Q08331, Q14257, Q15293, Q28BT4, Q2KJ39, Q3T0K1, Q3ZBY3, Q4U471, Q5R767, Q5R8Z6, Q5RDD8, Q62703, Q659X0, Q6EV76, Q6EV77, Q6IP82, Q6IQP3, Q6P8Y1

Diamond homologs: D4QD81, J9HGJ1, Q5R8Z6, Q8K5B2, Q8K5B3, Q8NI22, P97586, Q8R1U2, Q99674

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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
COPI-dependent Golgi-to-ER retrograde traffic	5	23.1×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
endoplasmic reticulum to Golgi vesicle-mediated transport	6	26.3×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	7
Uncertain significance	138
Likely benign	35
Benign	49

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1073084	NC_000002.11:g.(?47168661)(47238594_?)del	Pathogenic
2426554	NC_000002.11:g.(?47132602)(47206066_?)del	Pathogenic
2819608	NM_020458.4(TTC7A):c.176del (p.Pro59fs)	Pathogenic
2866	NM_139279.6(MCFD2):c.309+1G>A	Pathogenic
2867	NM_139279.6(MCFD2):c.103del (p.Gln35fs)	Pathogenic
2868	NM_139279.6(MCFD2):c.249del (p.Asp83fs)	Pathogenic
2869	NM_139279.6(MCFD2):c.265_272del (p.Asp89fs)	Pathogenic
2870	NM_139279.6(MCFD2):c.387C>G (p.Asp129Glu)	Pathogenic
2871	NM_139279.6(MCFD2):c.407T>C (p.Ile136Thr)	Pathogenic
2872	NM_139279.6(MCFD2):c.241G>T (p.Asp81Tyr)	Pathogenic
988519	NM_020458.4(TTC7A):c.76dup (p.Trp26fs)	Pathogenic
2503811	NM_020458.4(TTC7A):c.8del (p.Ala3fs)	Likely pathogenic
2865	NM_139279.6(MCFD2):c.149+5G>A	Likely pathogenic
627205	NM_139279.6(MCFD2):c.379_380dup (p.Asp127fs)	Likely pathogenic
800824	NM_139279.6(MCFD2):c.47T>C (p.Leu16Pro)	Likely pathogenic
812908	NM_139279.6(MCFD2):c.-6-1668_*2631del	Likely pathogenic
988852	NM_139279.6(MCFD2):c.364G>A (p.Asp122Asn)	Likely pathogenic
996288	NM_020458.4(TTC7A):c.138dup (p.Asn47Ter)	Likely pathogenic

SpliceAI

720 predictions. Top by Δscore:

Variant	Effect	Δscore
2:46907805:CCTA:C	donor_loss	1.0000
2:46907806:CTAC:C	donor_loss	1.0000
2:46907807:TAC:T	donor_loss	1.0000
2:46907808:ACCT:A	donor_gain	1.0000
2:46907809:CCTC:C	donor_gain	1.0000
2:46907811:T:TA	donor_gain	1.0000
2:46909021:A:AC	donor_gain	1.0000
2:46909022:C:CC	donor_gain	1.0000
2:46909022:CT:C	donor_gain	1.0000
2:46915720:CACC:C	donor_loss	1.0000
2:46915721:AC:A	donor_gain	1.0000
2:46915722:CC:C	donor_gain	1.0000
2:46907965:TATGC:T	acceptor_gain	0.9900
2:46907967:TGC:T	acceptor_gain	0.9900
2:46907970:C:CC	acceptor_gain	0.9900
2:46915718:CTCA:C	donor_loss	0.9900
2:46915721:A:AC	donor_gain	0.9900
2:46915722:C:CC	donor_gain	0.9900
2:46915728:CGGT:C	donor_gain	0.9900
2:46941723:CCGGT:C	donor_loss	0.9900
2:46941724:CGGTG:C	donor_loss	0.9900
2:46941726:G:A	donor_loss	0.9900
2:46941726:G:GG	donor_gain	0.9900
2:46941727:TGAG:T	donor_loss	0.9900
2:46941728:G:GG	donor_loss	0.9900
2:46905465:A:AC	donor_gain	0.9800
2:46905466:C:CC	donor_gain	0.9800
2:46907969:CCTAA:C	acceptor_loss	0.9800
2:46907970:C:CG	acceptor_loss	0.9800
2:46907971:T:G	acceptor_loss	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000053501 (2:46940820 G>A,C), RS1000101452 (2:46924565 C>G), RS1000118808 (2:46935059 A>G), RS1000283304 (2:46919215 A>G), RS1000284500 (2:46918980 A>G), RS1000463991 (2:46924411 C>G), RS1000499305 (2:46906129 T>C), RS1000506179 (2:46920714 A>C), RS1000622157 (2:46920470 C>T), RS1000685787 (2:46925762 T>A,C), RS1000690197 (2:46930055 G>A,C), RS1000739183 (2:46940062 G>T), RS1000740253 (2:46935130 A>G,T), RS1000795271 (2:46933896 G>A), RS1000812044 (2:46941218 G>C,T)

Disease associations

OMIM: gene MIM:607788 | disease phenotypes: MIM:243150, MIM:227300, MIM:613625

GenCC curated gene-disease

Disease	Classification	Inheritance
factor 5 and Factor VIII, combined deficiency of, 2	Definitive	Autosomal recessive
combined deficiency of factor V and factor VIII	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
factor 5 and Factor VIII, combined deficiency of, 2	Definitive	AR

Mondo (8): multiple intestinal atresia (MONDO:0009465), gastrointestinal defect and immunodeficiency syndrome (MONDO:0030831), factor V and factor VIII, combined deficiency of, type 1 (MONDO:0009206), factor 5 and Factor VIII, combined deficiency of, 2 (MONDO:0013331), thrombocytopenia (MONDO:0002049), gastrointestinal defects and immunodeficiency syndrome 1 (MONDO:0800030), severe combined immunodeficiency (MONDO:0015974), combined deficiency of factor V and factor VIII (MONDO:0018175)

Orphanet (4): Isolated multiple intestinal atresia (Orphanet:2300), Combined deficiency of factor V and factor VIII (Orphanet:35909), Combined immunodeficiency-multiple intestinal atresia (Orphanet:436252), Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

20 total (21 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000978	Bruising susceptibility
HP:0001934	Persistent bleeding after trauma
HP:0002149	Hyperuricemia
HP:0002170	Intracranial hemorrhage
HP:0002239	Gastrointestinal hemorrhage
HP:0003077	Hyperlipidemia
HP:0003125	Reduced factor VIII activity
HP:0003225	Reduced coagulation factor V activity
HP:0003645	Prolonged partial thromboplastin time
HP:0004846	Prolonged bleeding after surgery
HP:0005261	Joint hemorrhage
HP:0006298	Prolonged bleeding after dental extraction
HP:0008151	Prolonged prothrombin time
HP:0011889	Bleeding with minor or no trauma
HP:0030137	Prolonged bleeding following circumcision
HP:0004430	Severe combined immunodeficiency

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000635_23	Response to statin therapy	2.000000e-06
GCST008156_65	Hip circumference adjusted for BMI	4.000000e-06
GCST008162_102	Hip circumference	6.000000e-06
GCST90002396_203	Mean reticulocyte volume	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C562441	Intestinal Atresia, Multiple (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	6
Cyclosporine	increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
bisphenol S	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation, affects expression	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
uranyl acetate	affects expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1WX	Abcam HeLa MCFD2 KO	Cancer cell line	Female
CVCL_E1N3	HyCyte THP-1 KO-hMCFD2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT