RHBDD3

protein-coding

rhomboid domain containing 3, the group of Rhomboid family

Gene summary

Predicted to enable serine-type endopeptidase activity. Predicted to act upstream of or within several processes, including liver development; negative regulation of natural killer cell activation; and positive regulation of protein catabolic process. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

C22orf3

MANE transcript

NM_012265.3

Inheritance

—

ClinVar variants

U:73B:10

Top phenotype

EBV-positive nodal T- and NK-cell lymphoma

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr22:29,259,872-29,268,209

External References & Databases

Ensembl (ENSG00000100263)

Transcript & Mutation Effects

hg38 • Region Span ~8.3 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 RHBDD3 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 77

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012265.3. 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			1 clinvar	1 clinvar		2
missense			69 clinvar	9 clinvar		78
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	73	10	0	83

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012265.3	RefSeq	NP_036397.1	5	MANE Select
ENST00000216085.12	Ensembl	ENSP00000216085.7	5	MANE Select
NM_001329536.1	RefSeq	NP_001316465.1	5	Standard
ENST00000406335.1	Ensembl	ENSP00000384113.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

MAPK cascade
liver development
regulation of acute inflammatory response
proteolysis
response to xenobiotic stimulus

Molecular Function

serine-type endopeptidase activity

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216085
Coding exons: 5
Length: 8358
Individuals with no LoFs: 123595
Homozygous LoFs: 14
Heterozygous LoFs: 1906
Defined: 125515
p: 0.00768

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.102	197	201	0.980	0.0000120	2275
Missense (PolyPhen)		56	60.707	0.92247		801
Synonymous	0.373	95	99.7	0.952	0.00000622	917
Loss of Function	0.921	8	11.3	0.705	5.59e-7	125

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0019	0.0018	notable
Latino/Admixed American	0.0018	0.0018	notable
Ashkenazi Jewish	0.0071	0.0070	notable
East Asian	0	0.0	absent
Finnish	0.010	0.0099	notable
European (Non-Finnish)	0.013	0.013	notable
South Asian	0.00083	0.00078	rare
Other	0.0089	0.0085	notable

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0868

Intolerance Scores

LoFtool: 0.703
RVIS EVS: -0.16
RVIS percentile EVS: 42.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.710

Gene Damage Prediction

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