MEGF8

Summary

MEGF8 (multiple EGF like domains 8, HGNC:3233) is a protein-coding gene on chromosome 19q13.2, encoding Multiple epidermal growth factor-like domains protein 8 (Q7Z7M0). Acts as a negative regulator of hedgehog signaling.

The protein encoded by this gene is a single-pass type I membrane protein of unknown function that contains several EGF-like domains, Kelch repeats, and PSI domains. Defects in this gene are a cause of Carpenter syndrome 2. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1954 — RefSeq curated summary.

At a glance

• Gene–disease (curated): MEGF8-related Carpenter syndrome (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 1,260 total — 21 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 103
• MANE Select transcript: NM_001271938

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3233
Approved symbol	MEGF8
Name	multiple EGF like domains 8
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	SBP1, FLJ22365
Ensembl gene	ENSG00000105429
Ensembl biotype	protein_coding
OMIM	604267
Entrez	1954

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000251268, ENST00000334370, ENST00000378073, ENST00000593647, ENST00000593840, ENST00000598762, ENST00000599787

RefSeq mRNA: 2 — MANE Select: NM_001271938 NM_001271938, NM_001410

CCDS: CCDS12604, CCDS62693

Canonical transcript exons

ENST00000251268 — 42 exons

Exon	Start	End
ENSE00000709280	42369531	42369723
ENSE00000709282	42368843	42369002
ENSE00000709286	42363048	42363262
ENSE00000709290	42362090	42362213
ENSE00000709292	42360775	42361006
ENSE00000709293	42359098	42359242
ENSE00000709296	42358144	42358307
ENSE00000709299	42357404	42357584
ENSE00000709302	42356774	42356981
ENSE00000709308	42355758	42356005
ENSE00000709310	42354588	42354720
ENSE00000709312	42353775	42354024
ENSE00000709314	42353465	42353675
ENSE00000709316	42352928	42353127
ENSE00000847280	42358787	42358954
ENSE00000847282	42371350	42371482
ENSE00001114924	42356335	42356453
ENSE00001114929	42356083	42356193
ENSE00001114934	42368455	42368662
ENSE00001114967	42362384	42362597
ENSE00001162737	42352208	42352456
ENSE00001399735	42348272	42348472
ENSE00001406147	42349499	42349699
ENSE00001407138	42351648	42351761
ENSE00001409824	42343477	42343631
ENSE00001411823	42351216	42351334
ENSE00001414966	42351429	42351560
ENSE00001416200	42343954	42344073
ENSE00001416971	42337084	42337206
ENSE00001427077	42344441	42344585
ENSE00001428366	42344670	42344833
ENSE00001433179	42350148	42350384
ENSE00001641788	42375507	42378765
ENSE00002215289	42334007	42334213
ENSE00002216184	42335297	42335385
ENSE00002268993	42335931	42336346
ENSE00002284165	42336807	42336952
ENSE00002298851	42335035	42335215
ENSE00002312726	42333605	42333768
ENSE00003114512	42325635	42326430
ENSE00003542234	42370189	42370359
ENSE00003681528	42370701	42370831

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 93.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8150 / max 88.1562, expressed in 1775 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176159	9.7803	1720
176158	2.9212	1345
176161	0.7754	468
176160	0.2954	133
176163	0.0427	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	93.07	gold quality
middle temporal gyrus	UBERON:0002771	92.87	gold quality
prefrontal cortex	UBERON:0000451	92.20	gold quality
right frontal lobe	UBERON:0002810	92.10	gold quality
tendon of biceps brachii	UBERON:0008188	91.78	silver quality
frontal pole	UBERON:0002795	91.62	gold quality
primary visual cortex	UBERON:0002436	90.85	gold quality
occipital lobe	UBERON:0002021	90.46	gold quality
entorhinal cortex	UBERON:0002728	90.40	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.40	gold quality
frontal cortex	UBERON:0001870	90.38	gold quality
frontal lobe	UBERON:0016525	90.38	gold quality
superior frontal gyrus	UBERON:0002661	90.36	gold quality
neocortex	UBERON:0001950	90.27	gold quality
parotid gland	UBERON:0001831	90.21	gold quality
cerebellar vermis	UBERON:0004720	90.16	gold quality
parietal lobe	UBERON:0001872	90.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.97	gold quality
nucleus accumbens	UBERON:0001882	89.86	gold quality
cingulate cortex	UBERON:0003027	89.83	gold quality
anterior cingulate cortex	UBERON:0009835	89.75	gold quality
stromal cell of endometrium	CL:0002255	89.74	gold quality
postcentral gyrus	UBERON:0002581	89.74	gold quality
ganglionic eminence	UBERON:0004023	89.60	gold quality
cerebellar cortex	UBERON:0002129	89.52	gold quality
cerebral cortex	UBERON:0000956	89.44	gold quality
cerebellar hemisphere	UBERON:0002245	89.42	gold quality
paraflocculus	UBERON:0005351	89.27	gold quality
temporal lobe	UBERON:0001871	89.20	gold quality
cerebellum	UBERON:0002037	89.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BMP4	Unknown

miRNA regulators (miRDB)

58 targeting MEGF8, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914

Literature-anchored findings (GeneRIF, showing 3)

• mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. (PMID:23063620)
• Role and mechanism of miR-871-3p/Megf8 in regulating formaldehyde-induced cardiomyocyte inflammation and congenital heart disease. (PMID:38039718)
• The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients. (PMID:38760421)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	megf8	ENSDARG00000079751
mus_musculus	Megf8	ENSMUSG00000045039
rattus_norvegicus	Megf8	ENSRNOG00000052687

Paralogs (27): USH2A (ENSG00000042781), LAMC3 (ENSG00000050555), LAMA3 (ENSG00000053747), LAMC2 (ENSG00000058085), NTN1 (ENSG00000065320), NTN4 (ENSG00000074527), ATRN (ENSG00000088812), LAMB4 (ENSG00000091128), LAMB1 (ENSG00000091136), LAMA1 (ENSG00000101680), MEGF9 (ENSG00000106780), ATRNL1 (ENSG00000107518), LAMA4 (ENSG00000112769), LAMA5 (ENSG00000130702), LAMC1 (ENSG00000135862), NTN5 (ENSG00000142233), HSPG2 (ENSG00000142798), TMEFF2 (ENSG00000144339), NTN3 (ENSG00000162068), NTNG1 (ENSG00000162631), EGFLAM (ENSG00000164318), LAMB2 (ENSG00000172037), AGRN (ENSG00000188157), NTNG2 (ENSG00000196358), LAMA2 (ENSG00000196569), LAMB3 (ENSG00000196878), TMEFF1 (ENSG00000241697)

Protein

Protein identifiers

Multiple epidermal growth factor-like domains protein 8 — Q7Z7M0 (reviewed: Q7Z7M0)

Alternative names: Epidermal growth factor-like protein 4

All UniProt accessions (4): Q7Z7M0, F5GZG7, M0QZL2, M0R0Q0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a negative regulator of hedgehog signaling.

Subcellular location. Membrane.

Disease relevance. Carpenter syndrome 2 (CRPT2) [MIM:614976] An autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z7M0-1	1	yes
Q7Z7M0-2	2

RefSeq proteins (2): NP_001258867, NP_001401 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR000859	CUB_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002049	LE_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR016201	PSI	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024731	NELL2-like_EGF	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR056737	Beta-prop_ATRN-MKLN-like	Domain
IPR056863	LMN_ATRN_NET-like_EGF	Domain

Pfam: PF00053, PF00431, PF01437, PF07645, PF12947, PF24973, PF24981

UniProt features (85 total): disulfide bond 32, domain 18, repeat 12, glycosylation site 6, compositionally biased region 4, region of interest 3, sequence variant 3, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9QQS	ELECTRON MICROSCOPY	2.65
9QTY	ELECTRON MICROSCOPY	2.98
9QRU	ELECTRON MICROSCOPY	3.03
9QS6	ELECTRON MICROSCOPY	3.3
9QSH	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

No AlphaFold model available for Q7Z7M0 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (1): 1353

Disulfide bonds (32): 30–57, 142–152, 146–158, 174–184, 178–191, 193–202, 1078–1091, 1085–1100, 1102–1114, 1163–1171, 1165–1179, 1182–1191, 1194–1208, 1211–1224, 1213–1231, 1233–1242, 1245–1259, 1263–1302, 1336–1367, 1407–1421 …

Glycosylation sites (6): 50, 217, 1048, 1271, 2066, 2229

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 470 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEURON_RECOGNITION, PAX4_01, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE, AREB6_03, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS

GO Biological Process (30): embryonic heart tube morphogenesis (GO:0003143), smoothened signaling pathway (GO:0007224), regulation of gene expression (GO:0010468), protein ubiquitination (GO:0016567), embryonic limb morphogenesis (GO:0030326), BMP signaling pathway (GO:0030509), limb morphogenesis (GO:0035108), aorta development (GO:0035904), cell migration involved in gastrulation (GO:0042074), embryonic digit morphogenesis (GO:0042733), negative regulation of smoothened signaling pathway (GO:0045879), embryonic skeletal system morphogenesis (GO:0048704), positive regulation of axon extension involved in axon guidance (GO:0048842), epiboly involved in gastrulation with mouth forming second (GO:0055113), embryonic heart tube left/right pattern formation (GO:0060971), left/right pattern formation (GO:0060972), coronary vasculature development (GO:0060976), determination of heart left/right asymmetry (GO:0061371), pharyngeal arch artery morphogenesis (GO:0061626), protein-containing complex assembly (GO:0065003), determination of digestive tract left/right asymmetry (GO:0071907), craniofacial suture morphogenesis (GO:0097094), fasciculation of sensory neuron axon (GO:0097155), embryonic brain development (GO:1990403), morphogenesis of an epithelium (GO:0002009), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), embryonic morphogenesis (GO:0048598), skeletal system morphogenesis (GO:0048705), limb development (GO:0060173)

GO Molecular Function (2): calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (4): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), membrane (GO:0016020), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
embryonic morphogenesis	3
embryonic heart tube development	2
embryonic organ morphogenesis	2
heart development	2
heart morphogenesis	1
epithelial tube morphogenesis	1
cell surface receptor signaling pathway	1
gene expression	1
regulation of macromolecule biosynthetic process	1
protein modification by small protein conjugation	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
appendage morphogenesis	1
limb development	1
artery development	1
ameboidal-type cell migration	1
gastrulation	1
embryonic limb morphogenesis	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
skeletal system morphogenesis	1
embryonic skeletal system development	1
positive regulation of axon extension	1
regulation of axon extension involved in axon guidance	1
axon extension involved in axon guidance	1
positive regulation of chemotaxis	1
gastrulation with mouth forming second	1
epiboly	1
left/right pattern formation	1
regionalization	1
blood vessel development	1
determination of left/right symmetry	1
artery morphogenesis	1
pharyngeal system development	1
cellular component assembly	1
protein-containing complex organization	1
metal ion binding	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEGF8	MGRN1	O60291	849
MEGF8	GFI1B	Q5VTD9	786
MEGF8	SMARCD3	Q6STE5	761
MEGF8	MOSMO	Q8NHV5	662
MEGF8	RNF157	Q96PX1	575
MEGF8	EGF	P01133	504
MEGF8	TMEM145	Q8NBT3	480
MEGF8	CARD19	Q96LW7	452
MEGF8	MAGEB4	O15481	431
MEGF8	PRR19	A6NJB7	418
MEGF8	ZNF526	Q8TF50	408
MEGF8	DCLK3	Q9C098	394
MEGF8	ABTB1	Q969K4	392
MEGF8	LYZL6	O75951	384
MEGF8	CCDC88A	Q3V6T2	381

IntAct

67 interactions, top by confidence:

A	B	Type	Score
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
ANKRD46	ATRN	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
PSG3	MGRN1	psi-mi:“MI:0914”(association)	0.530
SPCS3	ENTPD6	psi-mi:“MI:0914”(association)	0.530
IGFBP4	MYCBP2	psi-mi:“MI:0914”(association)	0.530
IGFBP4	CETN3	psi-mi:“MI:0914”(association)	0.530
MGRN1	ATRN	psi-mi:“MI:0914”(association)	0.530
EDN3	MGRN1	psi-mi:“MI:0914”(association)	0.530
PSG8	MGRN1	psi-mi:“MI:0914”(association)	0.530
ATXN7	MEGF8	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	MEGF8	psi-mi:“MI:0915”(physical association)	0.510
MEGF8	ATXN7	psi-mi:“MI:0915”(physical association)	0.510
MEGF8	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
	MEGF8	psi-mi:“MI:0915”(physical association)	0.370
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
PSG1	IKBKB	psi-mi:“MI:0914”(association)	0.350
DEFB109B	CHST10	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (66): MEGF8 (Affinity Capture-RNA), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-RNA), MEGF8 (Affinity Capture-RNA), MEGF8 (Proximity Label-MS), MEGF8 (Two-hybrid), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS), MEGF8 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A0EQL2, D3YZF7, D7PDD4, O15533, O55237, O70394, O70540, O95866, P04278, P05111, P07994, P08689, P0C6B3, P0DP72, P15196, P17490, P18627, P40238, P55101, P60882, P97497, Q00657, Q08351, Q14393, Q14773, Q16671, Q3SWY4, Q5BK54, Q5NKT8, Q5TJE4, Q61790, Q61826, Q62588, Q6PZD2, Q6UVK1, Q6UWB1, Q7Z7M0, Q7Z7M1, Q86VR7

Diamond homologs: B3EX01, B8JI71, B8VIV4, C6KFA3, F1RWC3, O08628, O08859, O14786, O35276, O35375, O57382, O60462, O60494, O70244, O75074, O88204, P07898, P13497, P28824, P35443, P42662, P42664, P42674, P49744, P56677, P60882, P70412, P78504, P79795, P79953, P82279, P97333, P97607, P98065, P98066, P98069, P98072, P98074, Q06441, Q15113

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1260 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	21
Uncertain significance	608
Likely benign	422
Benign	79

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1162320	NM_001271938.2(MEGF8):c.5073del (p.Phe1692fs)	Pathogenic
2037327	NM_001271938.2(MEGF8):c.4451_4452delinsGCA (p.Leu1484fs)	Pathogenic
2081222	NM_001271938.2(MEGF8):c.3577C>T (p.Arg1193Ter)	Pathogenic
2128019	NM_001271938.2(MEGF8):c.3441del (p.Thr1149fs)	Pathogenic
2726282	NM_001271938.2(MEGF8):c.6301C>T (p.Arg2101Ter)	Pathogenic
3067104	NM_001271938.2(MEGF8):c.2499+1G>A	Pathogenic
3067105	NM_001271938.2(MEGF8):c.5844+1G>A	Pathogenic
3067111	NM_001271938.2(MEGF8):c.7992_7995del (p.Leu2665fs)	Pathogenic
3673024	NM_001271938.2(MEGF8):c.4227del (p.Gly1411fs)	Pathogenic
39846	NM_001271938.2(MEGF8):c.7300A>G (p.Ser2434Gly)	Pathogenic
39847	NM_001271938.2(MEGF8):c.1342C>T (p.Arg448Ter)	Pathogenic
39848	NM_001271938.2(MEGF8):c.595G>C (p.Gly199Arg)	Pathogenic
4294361	NM_001271938.2(MEGF8):c.634del (p.Ala212fs)	Pathogenic
4706279	NM_001271938.2(MEGF8):c.4108C>T (p.Arg1370Ter)	Pathogenic
4720696	NM_001271938.2(MEGF8):c.116_125del (p.Glu39fs)	Pathogenic
4723779	NM_001271938.2(MEGF8):c.2086C>T (p.Gln696Ter)	Pathogenic
4743508	NM_001271938.2(MEGF8):c.5253dup (p.Phe1752fs)	Pathogenic
4751010	NM_001271938.2(MEGF8):c.4885C>T (p.Arg1629Ter)	Pathogenic
4768373	NM_001271938.2(MEGF8):c.283C>T (p.Arg95Ter)	Pathogenic
561058	NM_001271938.2(MEGF8):c.1788+1G>C	Pathogenic
584047	NC_000019.10:g.(?42370701)(42370831_?)del	Pathogenic
1164007	NM_001271938.2(MEGF8):c.7970_7972del (p.Ser2657del)	Likely pathogenic
1217298	NM_001271938.2(MEGF8):c.7005+1G>T	Likely pathogenic
1703133	NM_001271938.2(MEGF8):c.3931G>T (p.Glu1311Ter)	Likely pathogenic
1804730	NM_001271938.2(MEGF8):c.7024G>T (p.Glu2342Ter)	Likely pathogenic
1915186	NM_001271938.2(MEGF8):c.3761+2T>C	Likely pathogenic
2017970	NM_001271938.2(MEGF8):c.1784_1788+3del	Likely pathogenic
2501122	NC_000019.9:g.(42830583_42837756)_(42838366_42839186)del	Likely pathogenic
2501123	NM_001271938.2(MEGF8):c.1741C>T (p.Gln581Ter)	Likely pathogenic
3067103	NM_001271938.2(MEGF8):c.878T>C (p.Leu293Pro)	Likely pathogenic

SpliceAI

6510 predictions. Top by Δscore:

Variant	Effect	Δscore
19:42337080:CCAG:C	acceptor_loss	1.0000
19:42337081:CAGG:C	acceptor_loss	1.0000
19:42337082:A:AG	acceptor_gain	1.0000
19:42337082:A:AT	acceptor_loss	1.0000
19:42337082:AG:A	acceptor_gain	1.0000
19:42337082:AGG:A	acceptor_gain	1.0000
19:42337082:AGGG:A	acceptor_gain	1.0000
19:42337083:G:GG	acceptor_gain	1.0000
19:42337083:GG:G	acceptor_gain	1.0000
19:42337083:GGG:G	acceptor_gain	1.0000
19:42337083:GGGG:G	acceptor_gain	1.0000
19:42337203:GAGG:G	donor_gain	1.0000
19:42337204:AGGGT:A	donor_loss	1.0000
19:42337205:GG:G	donor_gain	1.0000
19:42337206:GG:G	donor_gain	1.0000
19:42337207:GTGA:G	donor_loss	1.0000
19:42337208:T:A	donor_loss	1.0000
19:42344069:GGGCT:G	donor_gain	1.0000
19:42344070:GGCTG:G	donor_gain	1.0000
19:42344669:GAGCA:G	acceptor_gain	1.0000
19:42344831:AAG:A	donor_loss	1.0000
19:42344832:AGGT:A	donor_loss	1.0000
19:42344833:GGT:G	donor_loss	1.0000
19:42344835:T:G	donor_loss	1.0000
19:42351331:GCCA:G	donor_gain	1.0000
19:42351332:CCA:C	donor_gain	1.0000
19:42351333:CA:C	donor_gain	1.0000
19:42351334:AG:A	donor_loss	1.0000
19:42351335:GT:G	donor_loss	1.0000
19:42351335:GTGA:G	donor_gain	1.0000

AlphaMissense

18277 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:42326420:G:C	W59C	1.000
19:42326420:G:T	W59C	1.000
19:42333656:A:T	E80V	1.000
19:42333657:G:C	E80D	1.000
19:42333657:G:T	E80D	1.000
19:42333658:T:A	C81S	1.000
19:42333658:T:C	C81R	1.000
19:42333659:G:C	C81S	1.000
19:42333667:G:C	D84H	1.000
19:42333667:G:T	D84Y	1.000
19:42333668:A:C	D84A	1.000
19:42333668:A:T	D84V	1.000
19:42334020:T:C	L122P	1.000
19:42334026:G:T	S124I	1.000
19:42334029:A:C	D125A	1.000
19:42334029:A:G	D125G	1.000
19:42334029:A:T	D125V	1.000
19:42334036:C:A	N127K	1.000
19:42334036:C:G	N127K	1.000
19:42334053:T:C	F133S	1.000
19:42336809:T:G	F416C	1.000
19:42337166:G:C	W491C	1.000
19:42337166:G:T	W491C	1.000
19:42344719:G:C	W661C	1.000
19:42344719:G:T	W661C	1.000
19:42351233:G:C	W918C	1.000
19:42351233:G:T	W918C	1.000
19:42351477:G:C	W968C	1.000
19:42351477:G:T	W968C	1.000
19:42351478:T:A	C969S	1.000

dbSNP variants (sampled 300 via entrez): RS1000064038 (19:42325842 G>A,T), RS1000177856 (19:42360533 C>T), RS1000179704 (19:42363323 C>T), RS1000298162 (19:42359465 T>C), RS1000323476 (19:42341567 G>A), RS1000326602 (19:42353656 G>A), RS1000469972 (19:42356524 C>A,G), RS1000541506 (19:42374241 C>A,T), RS1000546834 (19:42331309 T>A), RS1000580675 (19:42350825 C>A,G,T), RS1000657055 (19:42358610 C>T), RS1000709827 (19:42337715 C>T), RS1000730344 (19:42344210 T>C), RS1000763194 (19:42344411 A>C,G), RS1000971479 (19:42361240 C>A,T)

Disease associations

OMIM: gene MIM:604267 | disease phenotypes: MIM:614976, MIM:123100, MIM:603596, MIM:201000

GenCC curated gene-disease

Disease	Classification	Inheritance
MEGF8-related Carpenter syndrome	Definitive	Autosomal recessive
Carpenter syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
MEGF8-related Carpenter syndrome	Moderate	AR

Mondo (4): MEGF8-related Carpenter syndrome (MONDO:0013998), craniosynostosis (MONDO:0015469), polydactyly (MONDO:0021003), Carpenter syndrome (MONDO:0019012)

Orphanet (2): Carpenter syndrome (Orphanet:65759), Craniosynostosis (Orphanet:1531)

HPO phenotypes

103 total (30 of 103 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000049	Shawl scrotum
HP:0000054	Micropenis
HP:0000098	Tall stature
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000243	Trigonocephaly
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000262	Turricephaly
HP:0000263	Oxycephaly
HP:0000275	Narrow face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000475	Broad neck
HP:0000481	Abnormal cornea morphology

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D017689	Polydactyly	C05.660.585.600; C16.131.621.585.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	3
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Leflunomide	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment	1
Arsenic	affects methylation	1
Diazinon	decreases methylation	1
Gallic Acid	increases expression	1
Lead	affects splicing	1
Methapyrilene	increases methylation	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Valproic Acid	increases expression	1
Vanadium	increases expression	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis
NCT00001404	Not specified	COMPLETED	Phenotype and Etiology of Pallister-Hall Syndrome
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity