GSDMD

protein-coding

gasdermin D, the group of Gasdermins

Gene summary

Gasdermin D is a member of the gasdermin family. Members of this family appear to play a role in regulation of epithelial proliferation. Gasdermin D has been suggested to act as a tumor suppressor. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

Previous symbols:

GSDMDC1

MANE transcript

NM_024736.7

Inheritance

—

ClinVar variants

U:100B:15

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1

Max pathogenic AF

—

Genomic locus

chr8:143,553,207-143,563,062

External References & Databases

Ensembl (ENSG00000104518)

Transcript & Mutation Effects

hg38 • Region Span ~9.9 kb

Loading mutation effect viewer...

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 GSDMD variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 95

not providedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024736.7. 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			3 clinvar	4 clinvar	1 clinvar	8
missense			94 clinvar	6 clinvar	4 clinvar	104
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	100	10	5	115

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024736.7	RefSeq	NP_079012.3	10	MANE Select
ENST00000262580.9	Ensembl	ENSP00000262580.4	10	MANE Select
NM_001166237.1	RefSeq	NP_001159709.1	10	Standard
ENST00000525208.1	Ensembl	ENSP00000433263.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOD-like receptor signaling pathway - Homo sapiens (human)
Neutrophil degranulation
Innate Immune System
Immune System

Biological Process

inflammatory response
cytolysis
cellular response to extracellular stimulus
pore formation in membrane of other organism
neutrophil degranulation

Molecular Function

phosphatidylserine binding
protein binding
phosphatidylinositol-4,5-bisphosphate binding
phosphatidylinositol-4-phosphate binding
phosphatidic acid binding

Cellular Component

extracellular region
extracellular space
nucleoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000526406
Coding exons: 10
Length: 9856
Individuals with no LoFs: 125454
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125486
p: 0.000128

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.599	261	290	0.901	0.0000180	3039
Missense (PolyPhen)		74	89.647	0.82546		1062
Synonymous	-0.144	138	136	1.02	0.00000925	1009
Loss of Function	0.0190	20	20.1	0.995	9.41e-7	224

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.00013	0.000092	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00033	0.00033	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Gasdermin-D, N-terminal: Promotes pyroptosis in response to microbial infection and danger signals. Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 or CASP4 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:27418190). After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)- bisphosphate, as well as phosphatidylinositol (3,4,5)- bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine (PubMed:27281216). Homooligomerizes within the membrane and forms pores of 10 - 15 nanometers (nm) of inner diameter, possibly allowing the release of mature IL1B and triggering pyroptosis (PubMed:27418190, PubMed:27281216). Exhibits bactericidal activity. Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (PubMed:27281216). Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (By similarity). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27281216). {ECO:0000250|UniProtKB:Q9D8T2, ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26375259, ECO:0000269|PubMed:27281216, ECO:0000269|PubMed:27418190}.;

Recessive Scores

pRec: 0.0912

Intolerance Scores

LoFtool: 0.839
RVIS EVS: -0.09
RVIS percentile EVS: 47.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.475

Gene Damage Prediction

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