SEMA4D

protein-coding

semaphorin 4D, the group of Immunoglobulin like domain containing|Semaphorins|CD molecules

Gene summary

Enables identical protein binding activity; semaphorin receptor binding activity; and transmembrane signaling receptor activity. Involved in several processes, including ossification involved in bone maturation; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and regulation of neuron projection development. Located in plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

SEMAJ
C9orf164

MANE transcript

NM_001371194.2

Inheritance

—

ClinVar variants

U:134B:31

Top phenotype

SEMA4D-related disorder

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr9:89,360,787-89,498,130

External References & Databases

Ensembl (ENSG00000187764)

Transcript & Mutation Effects

hg38 • Region Span ~137.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SEMA4D variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 133

SEMA4D-related disorderTotal: 21

not providedTotal: 13

Anti-SEMA4D Monoclonal Antibody VX15/2503Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371194.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				14 clinvar	3 clinvar	17
missense			130 clinvar	10 clinvar	4 clinvar	144
nonsense			3 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	134	24	7	165

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 129 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371194.2	RefSeq	NP_001358123.1	14	MANE Select
ENST00000422704.7	Ensembl	ENSP00000388768.2	14	MANE Select
NM_001142287.2	RefSeq	NP_001135759.1	17	Standard
NM_001371195.1	RefSeq	NP_001358124.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sema4d	Danio rerio	Structure: trunk Quality: curved abnormal

Gene / Model

Organism

Observed Phenotype

sema4d

Danio rerio

Structure: trunk

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Developmental Biology
Sema4D mediated inhibition of cell attachment and migration
Sema4D induced cell migration and growth-cone collapse
Sema4D in semaphorin signaling

Biological Process

negative regulation of transcription by RNA polymerase II
neural crest cell migration
positive regulation of protein phosphorylation
immune response
cell adhesion

Molecular Function

transmembrane signaling receptor activity
signaling receptor binding
protein binding
semaphorin receptor binding
signaling receptor activity

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000450295
Coding exons: 14
Length: 137344
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.997	460	524	0.877	0.0000324	5644
Missense (PolyPhen)		88	158.38	0.55561		1720
Synonymous	0.451	222	231	0.962	0.0000165	1710
Loss of Function	4.79	6	37.8	0.159	0.00000186	447

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00027	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cell surface receptor for PLXN1B and PLXNB2 that plays an important role in cell-cell signaling. Promotes reorganization of the actin cytoskeleton and plays a role in axonal growth cone guidance in the developing central nervous system. Regulates dendrite and axon branching and morphogenesis. Promotes the migration of cerebellar granule cells and of endothelial cells. Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro). Promotes signaling via SRC and PTK2B/PYK2, which then mediates activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Interaction with PLXNB1 mediates activation of RHOA. {ECO:0000269|PubMed:16055703, ECO:0000269|PubMed:19788569, ECO:0000269|PubMed:20877282, ECO:0000269|PubMed:8876214}.;

Recessive Scores

pRec: 0.224

Intolerance Scores

LoFtool: 0.787
RVIS EVS: 0.12
RVIS percentile EVS: 62.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.725

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium