GPKOW

protein-coding

G-patch domain and KOW motifs, the group of Spliceosomal Bact complex|Spliceosomal P complex|NTC associated proteins|Spliceosomal C complex|G-patch domain containing

Gene summary

This gene encodes a putative RNA-binding protein containing G-patch and KOW (Kyprides, Ouzounis, Woese) domains. The encoded protein interacts directly with protein kinase A and protein kinase X and is also found associated with the spliceosome. [provided by RefSeq, Aug 2013]

MANE transcript

NM_015698.6

Inheritance

ClinVar variants

U:114B:11

Top phenotype

syndromic disease

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:49,113,407-49,123,735

External References & Databases

Ensembl (ENSG00000068394)

Transcript & Mutation Effects

hg38 • Region Span ~10.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

holoprosencephaly-hypokinesia-congenital contractures syndromeLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010610

Submitter: Illumina

holoprosencephaly-hypokinesia-congenital contractures syndromeMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010610

Submitter: ClinGen

The *GPKOW* gene is located on chromosome X at Xp11.23 and encodes the G-Patch Domain And KOW Motifs protein, a putative RNA-binding protein. *GPKOW* was first reported in relation to X-linked holoprosencephaly-hypokinesia-congenital contractures syndrome in 2017 (Carroll et al., PMID: 28612833). The syndrome is characterised by holoprosencephaly / microcephaly, intrauterine growth restriction, hypokinesia, and congenital contractures. Additional phenotypes include dysmorphic features, skeletal dysplasia, microphthalmia, macroglossia. Female carriers usually present with short stature and small head circumference. Evidence supporting this gene-disease relationship includes case-level data and experimental evidence. Six variants (missense, nonsense, frameshift and splice variants ) that have been reported in six probands in three publications and 2 ClinVar entries are included in this curation (PMIDs: 28612833, 32426895, 40221893, SCV006060217.1, SCV006060182.1). This gene-disease relationship is also supported by experimental evidence including model organism and biochemical function. A fruit fly animal model supports that this gene contributes to microphthalmia and reduced brain size (PMIDs: 40221893). Limited biochemical evidence of direct interaction with DHX16/hPRP2 and RNA supports *GPKOW*’s role in pre-mRNA splicing (PMID: 25296192). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date December 3, 2025 (SOP Version 11).

syndromic diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPKOW variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 55

not providedTotal: 14

GPKOW-related disorderTotal: 6

Holoprosencephaly-hypokinesia-congenital contractures syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015698.6. 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			9 clinvar	2 clinvar	2 clinvar	13
missense			91 clinvar	6 clinvar	1 clinvar	98
nonsense			4 clinvar			4
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	0	0	114	8	3	125

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015698.6	RefSeq	NP_056513.2	11	MANE Select
ENST00000156109.7	Ensembl	ENSP00000156109.5	11	MANE Select
ENST00000916257.1	Ensembl	ENSP00000586316.1	8	Standard
ENST00000916257.2	Ensembl	ENSP00000586316.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of RNA
mRNA Splicing - Major Pathway
mRNA Splicing
Processing of Capped Intron-Containing Pre-mRNA

Biological Process

mRNA splicing, via spliceosome

Molecular Function

RNA binding
protein binding

Cellular Component

nucleus
nucleoplasm
spliceosomal complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000156109
Coding exons: 11
Length: 9818
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.921	166	203	0.818	0.0000169	3055
Missense (PolyPhen)		41	59.273	0.69171		922
Synonymous	-0.228	79	76.5	1.03	0.00000584	999
Loss of Function	3.71	0	16.0	0.00	0.00000123	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA-binding protein involved in pre-mRNA splicing. {ECO:0000269|PubMed:25296192}.;

Recessive Scores

pRec: 0.0872

Intolerance Scores

LoFtool: 0.0403
RVIS EVS: -0.38
RVIS percentile EVS: 27.69

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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