GORAB

protein-coding

golgin, RAB6 interacting

Gene summary

This gene encodes a member of the golgin family, a group of coiled-coil proteins localized to the Golgi. The encoded protein may function in the secretory pathway. The encoded protein, which also localizes to the cytoplasm, was identified by interactions with the N-terminal kinase-like protein, and thus it may function in mitosis. Mutations in this gene have been associated with geroderma osteodysplastica. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

Previous symbols:

SCYL1BP1

MANE transcript

NM_152281.3

Inheritance

ClinVar variants

P:43U:123B:123

Top phenotype

Geroderma osteodysplasticum

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr1:170,531,819-170,553,834

External References & Databases

Ensembl (ENSG00000120370)

Transcript & Mutation Effects

hg38 • Region Span ~22.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

geroderma osteodysplasticumSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: PanelApp Australia

geroderma osteodysplasticumMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: Ambry Genetics

geroderma osteodysplasticumSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: Labcorp Genetics (formerly Invitae)

geroderma osteodysplasticumSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: Genomics England PanelApp

geroderma osteodysplasticumDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: ClinGen

*GORAB* was first reported in relation to geroderma osteodysplastica (GO), in 2008 (Hennies et al, PMID: 18997784). GO is an autosomal recessive segmental progeroid disorder that affects the skin, connective tissues, and bone. It is characterized by wrinkled skin, joint laxity, a prematurely aged facial appearance, severe osteoporosis leading to frequent fractures, malar and mandibular hypoplasia, variable growth retardation, and mild intellectual disability in some cases. GO is the only condition known to result from variants in *GORAB*. Twelve variants (7 nonsense, 3 frameshift, 2 missense) that have been reported in ten probands in four publications (Hennies et al, 2008 PMID: 18997784; Al-Dosari & Alkuraya, 2009, PMID: 19681135; Takeda et al, PMID: 28807865, 2017; Saad et al, 2024, PMID: 39619733) are included in this curation. Segregation evidence from Mennonite families was also included. A founder variant, c.367G>T (p.Glu123Ter), has been identified in that population (Hennies et al, 2008 PMID: 18997784). More evidence is available in the literature, but the maximum score for genetic evidence (>12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence including biochemical function and mouse models (total 2 points). *GORAB* encodes a protein that localizes to the trans Golgi where it interacts with RAB6, regulates the level of active TGF-β, and stabilizes the COPI complex. It has been shown to be important in COPI-mediated retrograde trafficking of transGolgi enzymes, including glycosyltransferases. Loss of *GORAB* function leads to defective protein glycosylation and disorganization of the extracellular matrix, consistent with the clinical phenotype. Null mouse models die early in life and do not have a skin phenotype. Mouse models with conditional loss of Gorab in osteoblasts recapitulate the bone phenotype in human, with osteoporosis and multiple long bone fractures (Yang et al, 2017, PMID: 29108851; Chan et al, 2018, PMID: 29561836; Chan et al, 2024, 39234801). In summary, there is definitive evidence supporting the relationship between *GORAB* and geroderma osteodysplastica, and autosomal recessive segmental progeroid condition. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on July 3, 2025 (SOP Version #11].

geroderma osteodysplasticumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: Orphanet

geroderma osteodysplasticumDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: G2P

Clinical Genomic Database (CGD)

Geroderma osteodysplasticumAR

Manifestation: Dermatologic; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 631850; 474638; 3236370; 8213917; 8723088; 9018419; 18997784; 18348262; 19681135; 21204221

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GORAB variants in ClinVar

5 Conditions Cataloged

not providedTotal: 297

Geroderma osteodysplasticaTotal: 59

Inborn genetic diseasesTotal: 50

not specifiedTotal: 16

GORAB-related disorderTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152281.3. 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				114 clinvar	2 clinvar	116
missense	1 clinvar		118 clinvar	7 clinvar		126
nonsense	10 clinvar	4 clinvar	2 clinvar			16
start loss		1 clinvar	1 clinvar			2
frameshift	18 clinvar	5 clinvar	1 clinvar			24
splice donor/acceptor (+/-2bp)		4 clinvar	1 clinvar			5
Total	29	14	123	121	2	289

Highest pathogenic variant AF is 0.00014994027

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152281.3	RefSeq	NP_689494.3	5	MANE Select
ENST00000367763.8	Ensembl	ENSP00000356737.4	5	MANE Select
NM_001146039.2	RefSeq	NP_001139511.2	4	Standard
NM_001320252.2	RefSeq	NP_001307181.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

p53 signaling pathway - Homo sapiens (human)

Biological Process

hair follicle morphogenesis
positive regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning
non-motile cilium assembly

Molecular Function

protein binding

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367763
Coding exons: 5
Length: 21318
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125746
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.180	223	216	1.03	0.0000123	2575
Missense (PolyPhen)		64	71.77	0.89173		858
Synonymous	-1.08	91	78.8	1.16	0.00000429	751
Loss of Function	1.61	11	18.4	0.596	0.00000111	185

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00013	rare
South Asian	0.00016	0.00016	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Geroderma osteodysplasticum (GO) [MIM:231070]: A rare autosomal recessive disorder characterized by lax, wrinkled skin, joint laxity and a typical face with a prematurely aged appearance. Skeletal signs include severe osteoporosis leading to frequent fractures, malar and mandibular hypoplasia and a variable degree of growth retardation. {ECO:0000269|PubMed:18997784}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0895

Intolerance Scores

LoFtool: 0.887
RVIS EVS: -0.47
RVIS percentile EVS: 23.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.239

Gene Damage Prediction

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