GRHL3

Summary

GRHL3 (grainyhead like transcription factor 3, HGNC:25839) is a protein-coding gene on chromosome 1p36.11, encoding Grainyhead-like protein 3 homolog (Q8TE85). Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin.

This gene encodes a member of the grainyhead family of transcription factors. The encoded protein may function as a transcription factor during development, and has been shown to stimulate migration of endothelial cells. Multiple transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 57822 — RefSeq curated summary.

At a glance

• Gene–disease (curated): GRHL3-related orofacial clefting (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 271 total — 14 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 34
• Transcription factor: yes — 31 downstream targets (CollecTRI)
• MANE Select transcript: NM_198173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25839
Approved symbol	GRHL3
Name	grainyhead like transcription factor 3
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	SOM
Ensembl gene	ENSG00000158055
Ensembl biotype	protein_coding
OMIM	608317
Entrez	57822

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000236255, ENST00000350501, ENST00000356046, ENST00000361548, ENST00000461318, ENST00000524724, ENST00000528064, ENST00000528181, ENST00000530984, ENST00000689444, ENST00000690803, ENST00000692334

RefSeq mRNA: 4 — MANE Select: NM_198173 NM_001195010, NM_021180, NM_198173, NM_198174

CCDS: CCDS251, CCDS252, CCDS44088, CCDS53284

Canonical transcript exons

ENST00000361548 — 16 exons

Exon	Start	End
ENSE00002199818	24319357	24319568
ENSE00003472328	24342694	24342772
ENSE00003489938	24336482	24336827
ENSE00003547455	24337078	24337151
ENSE00003550253	24337992	24338103
ENSE00003587546	24350058	24350122
ENSE00003598119	24342892	24343025
ENSE00003607868	24346553	24346641
ENSE00003620120	24337636	24337789
ENSE00003641493	24331426	24331612
ENSE00003650381	24339668	24339762
ENSE00003654038	24344897	24344931
ENSE00003659215	24334645	24334706
ENSE00003670244	24347468	24347553
ENSE00003670273	24342115	24342273
ENSE00003901446	24354374	24355318

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 98.57.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9308 / max 190.6342, expressed in 516 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1383	1.3121	332
1385	0.7851	252
1386	0.2777	163
1382	0.2379	135
1387	0.1758	68
1384	0.1005	44
1381	0.0416	15

Top tissues by expression

245 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.57	gold quality
esophagus mucosa	UBERON:0002469	96.54	gold quality
gingival epithelium	UBERON:0001949	95.13	gold quality
pharyngeal mucosa	UBERON:0000355	95.07	gold quality
gingiva	UBERON:0001828	94.78	gold quality
esophagus squamous epithelium	UBERON:0006920	93.75	gold quality
oral cavity	UBERON:0000167	93.34	gold quality
skin of abdomen	UBERON:0001416	92.43	gold quality
secondary oocyte	CL:0000655	91.48	gold quality
upper arm skin	UBERON:0004263	91.48	silver quality
skin of leg	UBERON:0001511	91.12	gold quality
zone of skin	UBERON:0000014	90.44	gold quality
upper leg skin	UBERON:0004262	90.13	gold quality
mammalian vulva	UBERON:0000997	88.06	gold quality
oocyte	CL:0000023	86.67	gold quality
penis	UBERON:0000989	86.47	gold quality
body of tongue	UBERON:0011876	86.38	gold quality
vagina	UBERON:0000996	82.68	gold quality
tongue	UBERON:0001723	79.53	gold quality
tonsil	UBERON:0002372	79.40	gold quality
urinary bladder	UBERON:0001255	79.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.65	gold quality
epithelium of nasopharynx	UBERON:0001951	78.44	silver quality
skin of hip	UBERON:0001554	77.38	gold quality
sperm	CL:0000019	76.86	silver quality
amniotic fluid	UBERON:0000173	75.53	silver quality
nipple	UBERON:0002030	74.81	gold quality
esophagus	UBERON:0001043	73.28	gold quality
superior surface of tongue	UBERON:0007371	72.95	gold quality
palpebral conjunctiva	UBERON:0001812	72.36	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

31 targets.

Target	Regulation
ABCB1
ACHE
ANGPT1
ATM
AXIN2
BAX
BDNF
BIK
CALCA
CDH1
CDKN2A
CLDN7
HEY1
HP
INS
KRT5
MIR21
NOS1
NOTCH1
OGA
PTEN
RB1
SMAD7
SMYD1
TAT
TFAP2A
TIAM1
TNFRSF11A
UBE2D3
UPK2

Upstream regulators (CollecTRI, top): IRF6, KLF5

miRNA regulators (miRDB)

56 targeting GRHL3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4481	100.00	66.42	1669
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-556-3P	99.74	68.75	1203

Literature-anchored findings (GeneRIF, showing 39)

• Data report the identification of Sister-of-Mammalian Grainyhead (SOM), which is phylogenetically aligned with grainyhead protein, and like grainyhead encodes a highly conserved developmental transcription factor. [Sister-of-Mammalian Grainyhead] (PMID:12549979)
• GRHL3 strongly stimulated primary endothelial cell migration, suggesting that it is a putative tumor-angiogenesis factor. (PMID:18814840)
• loss of GRHL3 may result in endothelial dysfunction in vivo. (PMID:21856281)
• decreased Grhl3 expression contributes to tumor progression and upregulation of the oncomir miR-21 in squamous cell carcinoma of the skin. (PMID:22614019)
• we define a previously unknown role for the transcription factor GRHL3 in the recruitment of a trxG complex to promoters of genes, leading to increased H3K4 methylation and gene expression (PMID:22829784)
• In human keratinocytes, IRF6 bound conserved elements near the GRHL3 promoter, with one of these elements having enhancer activity. (PMID:22931925)
• The splice variant-derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes. (PMID:23685552)
• Our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. (PMID:24360809)
• our results indicate predominant GRHL3 expression in breast cancers (PMID:24363083)
• We defined a novel molecular signature in mammalian HNSCC, suggesting new treatment strategies targeting the GRHL3/GSK3B/c-MYC proto-oncogenic network. (PMID:26063791)
• GRHL1, GRHL2, and GRHL3 have roles in cellular proliferation, differentiation, adhesion, and polarity and may promote cancer or be tumor suppressors [review] (PMID:26069269)
• GRHL3 expression may be useful as a prognostic factor. (PMID:26797800)
• findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells (PMID:26837418)
• We discovered a genome-wide significant association with a missense variant in GRHL3 and replicated the result in an independent sample of case and control subjects. In both samples, rs41268753 conferred increased risk for cleft palate. (PMID:27018472)
• We identified both rare dominant mutations and a common risk variant in the coding region of GRHL3 as causative in individuals with nonsyndromic cleft palate only. (PMID:27018475)
• Study genotyped 10 tag SNPs covering GRHL3 and performed association analysis with nonsyndromic cleft lip with or without cleft palate in 504 cases and 455 healthy controls; preliminary results identified rs10903078, rs4638975, and a haplotype rs10903078-rs6659209 of GRHL3 that exceeded the significance threshold (p<0.05), though none survived Bonferroni correction for multiple comparisons. (PMID:27129939)
• No association found between two GRHL3 SNPs (rs2486668 and rs545809) and non-syndromic orofacial clefts in the Han Chinese cohort. (PMID:27459192)
• The data suggest that IRF6, TFAP2A, and GRHL3, among others, are shared in neural tube and orofacial development. (PMID:27933721)
• Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations (PMID:28276201)
• ey epidermal differentiation transcription factor genes, including GRHL3, are located within super-enhancers, and many of these transcription factors in turn bind to and regulate super-enhancers. (PMID:28445475)
• All of these processes involve epithelial-mesencyhmal transition (EMT), MET or a sequence of both, suggesting that the GRHL factors((GRHL1, GRHL2 and GRHL3), could potentially affect tumor initiation and progression via EMT (PMID:28714958)
• mutations contribute to the risk of nonsyndromic cleft palate only in the African population (PMID:28886269)
• The down-regulation of GRHL3 in vitro could inhibit colorectal cancer cell activity and trigger cell cycle arrest at G0/G1 phase and apoptosis. (PMID:29270747)
• Non-melanoma skin cancer growth is accompanied by coordinated reduced expression of epidermal differentiation genes: GRHL1 and GRHL3, which may be regulated by miR-21-3p and -5p, respectively. Some potentially damaging single nucleotide polymorphisms in GRHL genes occur with altered frequencies in NMSC patients, and they may in particular impair the expression of GRHL3 gene or functioning of encoded protein (PMID:29301499)
• We identified rare damaging variants in four genes known to be mutated in syndromic lip and/or cleft palate (syCL/P) : TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their lip and/or cleft palate (CL/P). (PMID:29500247)
• Hypomethylation of GRHL3 in central nervous tissue is associated with neural tube defects. (PMID:29587534)
• Grainyhead-like 3 transcription factor is phosphorylated at many residues in cells. Cleft palate associated single nucleotide polymorphism abolishes threonine 454 phosphorylation. This residue is phosphorylated by the p38 MAP kinase. Threonine 454 is essential for regulation of GRHL3 activity by the p38 pathway. (PMID:29702134)
• Deletion of the transcription factor GRHL3 in the skin initiates a chemokine responsive signal leading to keratinocytes hyperproliferation and a pro-tumorigenic state. (PMID:30341279)
• In the case-control study, significant associations were found between C27G genetic variants on rs2486668 and risk for spina bifida and encephalocele, respectively, under different genetic models. GG genotype on rs2486668 was associated with increased risk for spina bifida, with a RR of 2.15 (95% CI: 1.20-3.83).The GRHL3 C67G missense variant may increase the risk for spina bifida and encephalocele phenotypes. (PMID:31332962)
• Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration. (PMID:33469008)
• The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity. (PMID:33775911)
• Grainyhead-Like 3 Influences Migration and Invasion of Urothelial Carcinoma Cells. (PMID:33803949)
• Association analysis of SNPs in GRHL3, FAF1, and KCNJ2 with NSCPO sub-phenotypes in Han Chinese. (PMID:34255421)
• Novel GRHL3 Variants in a South African Cohort With Cleft Lip and Palate. (PMID:34459660)
• GRHL3 Promotes Tumor Growth and Metastasis via the MEK Pathway in Colorectal Cancer. (PMID:34888136)
• Genetic markers for non-syndromic orofacial clefts in populations of European ancestry: a meta-analysis. (PMID:35075162)
• A Comprehensive Genetic Analysis of Slovenian Families with Multiple Cases of Orofacial Clefts Reveals Novel Variants in the Genes IRF6, GRHL3, and TBX22. (PMID:36901693)
• The GRHL3-regulated long non-coding RNA lnc-DC modulates keratinocytes differentiation by interacting with IGF2BP2 and up-regulating ZNF750. (PMID:38383230)
• Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes. (PMID:38429970)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	grhl3	ENSDARG00000078552
mus_musculus	Grhl3	ENSMUSG00000037188
rattus_norvegicus	Grhl3	ENSRNOG00000029427
drosophila_melanogaster	gem	FBGN0050011
caenorhabditis_elegans	grh-1	WBGENE00001707

Paralogs (5): GRHL2 (ENSG00000083307), TFCP2L1 (ENSG00000115112), GRHL1 (ENSG00000134317), TFCP2 (ENSG00000135457), UBP1 (ENSG00000153560)

Protein

Protein identifiers

Grainyhead-like protein 3 homolog — Q8TE85 (reviewed: Q8TE85)

Alternative names: Sister of mammalian grainyhead, Transcription factor CP2-like 4

All UniProt accessions (4): A0A8I5KUQ1, E9PLG9, E9PLT6, Q8TE85

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin. Binds directly to the consensus DNA sequence 5’-AACCGGTT-3’ acting as an activator and repressor on distinct target genes. xhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair. Exhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair but is essential to form the epidermal barrier with TGM3 as critical direct target gene among others. Despite being dispensable during normal epidermal homeostasis in the adulthood, is again required for barrier repair after immune-mediated epidermal damage, regulates distinct gene batteries in embryonic epidermal differentiation and adult epidermal barrier reformation after injury. Plays unique and cooperative roles with GRHL2 in establishing distinct zones of primary neurulation. Essential for spinal closure, functions cooperatively with GRHL2 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure. Also required for proper development of the oral periderm. No genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity.

Subunit / interactions. Homodimer, also forms heterodimers with GRHL1 and GRHL2. Interacts with LMO4.

Subcellular location. Nucleus.

Tissue specificity. Expressed in brain, colon, pancreas, placenta and kidney. Isoform 1 is expressed in lung and tonsil. Isoform 2 is prostate-specific.

Disease relevance. Van der Woude syndrome 2 (VWS2) [MIM:606713] An autosomal dominant developmental disorder characterized by lower lip pits, cleft lip and/or cleft palate. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. GRHL genes (GRHL1, GRHL2 and GRHL3) show a paradoxical lack of redundancy despite their extensive sequence identity in the DNA-binding and protein dimerization domains and the fact that the core consensus DNA binding sites are identical. They have related, but remarkably different functions during embryogenesis because of their differential spatiotemporal expression patterns during development.

Similarity. Belongs to the grh/CP2 family. Grainyhead subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8TE85-1	1	yes
Q8TE85-2	2
Q8TE85-3	3
Q8TE85-4	4
Q8TE85-5	5

RefSeq proteins (4): NP_001181939, NP_067003, NP_937816, NP_937817 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007604	CP2	Domain
IPR040167	TF_CP2-like	Family
IPR057520	GRHL1/CP2_C	Domain

Pfam: PF04516, PF25416

UniProt features (15 total): sequence variant 5, splice variant 4, sequence conflict 3, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TE85-F1	61.27	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 278 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, PEREZ_TP63_TARGETS, GCANCTGNY_MYOD_Q6, AREB6_03, RACCACAR_AML_Q6, GOBP_NEURAL_TUBE_DEVELOPMENT, GGGTGGRR_PAX4_03, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_WOUND_HEALING, GOBP_ECTODERM_DEVELOPMENT

GO Biological Process (17): establishment of planar polarity (GO:0001736), neural tube closure (GO:0001843), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), pattern specification process (GO:0007389), ectoderm development (GO:0007398), central nervous system development (GO:0007417), epidermis development (GO:0008544), positive regulation of gene expression (GO:0010628), regulation of actin cytoskeleton organization (GO:0032956), wound healing (GO:0042060), positive regulation of transcription by RNA polymerase II (GO:0045944), eyelid development in camera-type eye (GO:0061029), establishment of skin barrier (GO:0061436), cochlea morphogenesis (GO:0090103), gene expression (GO:0010467), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin DNA binding (GO:0031490), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), cilium (GO:0005929), actin cytoskeleton (GO:0015629)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
tissue development	2
regulation of transcription by RNA polymerase II	2
DNA binding	2
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	1
primary neural tube formation	1
tube closure	1
multicellular organism development	1
multicellular organismal process	1
nervous system development	1
system development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
response to wounding	1
tissue regeneration	1
positive regulation of DNA-templated transcription	1
camera-type eye development	1
anatomical structure development	1
skin epidermis development	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1
macromolecule biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
chromatin binding	1

Protein interactions and networks

STRING

1234 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRHL3	IRF6	O14896	809
GRHL3	TGM1	P22735	766
GRHL3	ZNF750	Q32MQ0	659
GRHL3	OVOL1	O14753	611
GRHL3	ARHGAP29	Q52LW3	559
GRHL3	PRKCG	P05129	547
GRHL3	PAX3	P23760	530
GRHL3	DLX3	O60479	528
GRHL3	KDM6B	O15054	520
GRHL3	RARB	P10826	498
GRHL3	KMT2D	O14686	495
GRHL3	PRKCE	Q02156	493
GRHL3	PRKCD	Q05655	493
GRHL3	PRKCB	P05127	491
GRHL3	SMARCA4	P51532	487

IntAct

19 interactions, top by confidence:

A	B	Type	Score
GRHL3	PRMT6	psi-mi:“MI:0915”(physical association)	0.510
GRHL3	PRMT5	psi-mi:“MI:0915”(physical association)	0.510
GRHL3	VSIG8	psi-mi:“MI:0915”(physical association)	0.400
CCL1	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
CXCL5	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
IFNA5	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
IFNA8	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
IL17F	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
IL21	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
IL37	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
PF4V1	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
TNFSF4	GRHL3	psi-mi:“MI:0915”(physical association)	0.370
GRHL3	PRMT1	psi-mi:“MI:0915”(physical association)	0.370
P		psi-mi:“MI:0914”(association)	0.350

BioGRID (17): VSIG8 (Affinity Capture-MS), GRHL3 (Two-hybrid), GRHL3 (Two-hybrid), GRHL3 (Two-hybrid), GRHL1 (Two-hybrid), GRHL3 (Two-hybrid), GRHL2 (Two-hybrid), GRHL2 (Reconstituted Complex), GRHL1 (Reconstituted Complex), GRHL3 (Reconstituted Complex), VSIG8 (Affinity Capture-MS), MACF1 (Cross-Linking-MS (XL-MS)), PRMT5 (Affinity Capture-Luminescence), PRMT6 (Affinity Capture-Luminescence), PRMT1 (Two-hybrid)

ESM2 similar proteins: A6QNP3, F1QJF4, F6Y9J3, O60308, P97874, Q02395, Q08D35, Q0VCR4, Q14B46, Q28E28, Q5BL87, Q5FWH3, Q5JTW2, Q5QNQ6, Q5R7T9, Q5U2R5, Q5XGX5, Q5XIZ9, Q60695, Q60949, Q6DDQ5, Q6GL23, Q6GL65, Q6GQ68, Q6IN01, Q6P950, Q7TMB3, Q803M0, Q80T23, Q80U87, Q812E4, Q86XI6, Q8BXR9, Q8C5W4, Q8C767, Q8C7M3, Q8GT06, Q8TDW5, Q8TE85, Q8VHQ7

Diamond homologs: G5EDF0, P13002, Q12800, Q3UNW5, Q4V860, Q5EY87, Q5FWH3, Q5M7R9, Q5PPL8, Q5RAR8, Q5RB16, Q6GL65, Q6ISB3, Q6NZH6, Q7T2U9, Q811S7, Q8K5C0, Q8TE85, Q921D9, Q9ERA0, Q9NZI5, Q9NZI6, Q9NZI7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
inflammatory response	6	18.9×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

271 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	7
Uncertain significance	129
Likely benign	38
Benign	59

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
101516	NM_198173.3(GRHL3):c.970_971insGT (p.Phe324fs)	Pathogenic
101517	NM_198173.3(GRHL3):c.1563_1566del (p.Glu522fs)	Pathogenic
101518	NM_198173.3(GRHL3):c.893G>A (p.Arg298His)	Pathogenic
101519	NM_198173.3(GRHL3):c.1419+1G>T	Pathogenic
1068818	NM_198173.3(GRHL3):c.1419+1G>A	Pathogenic
1172586	NM_198173.3(GRHL3):c.1172G>A (p.Arg391His)	Pathogenic
1706483	GRCh37/hg19 1p36.11(chr1:24531639-24749706)x1	Pathogenic
219244	NM_198173.3(GRHL3):c.840+1G>T	Pathogenic
219245	NM_198173.3(GRHL3):c.916dup (p.Arg306fs)	Pathogenic
219246	NM_198173.3(GRHL3):c.1285+2del	Pathogenic
3102301	NM_198173.3(GRHL3):c.934C>T (p.Gln312Ter)	Pathogenic
3247719	NC_000001.10:g.(?23395012)(24673151_?)del	Pathogenic
4266829	NM_198173.3(GRHL3):c.1047+1G>A	Pathogenic
465251	NM_198173.3(GRHL3):c.899G>A (p.Trp300Ter)	Pathogenic
1172584	NM_198173.3(GRHL3):c.22A>G (p.Arg8Gly)	Likely pathogenic
1879081	NM_198173.3(GRHL3):c.134_152dup (p.Asn51fs)	Likely pathogenic
2006242	NM_198173.3(GRHL3):c.204+2T>C	Likely pathogenic
208652	NM_198173.3(GRHL3):c.1795C>G (p.Leu599Val)	Likely pathogenic
3059162	NM_198173.3(GRHL3):c.847del (p.Val282_Val283insTer)	Likely pathogenic
3062261	NM_198173.3(GRHL3):c.1115del (p.Leu372fs)	Likely pathogenic
3235927	NM_198173.3(GRHL3):c.318dup (p.Thr107fs)	Likely pathogenic

SpliceAI

2450 predictions. Top by Δscore:

Variant	Effect	Δscore
1:24319567:GA:G	donor_gain	1.0000
1:24319569:G:GG	donor_gain	1.0000
1:24331610:ATGG:A	donor_loss	1.0000
1:24331612:GGT:G	donor_loss	1.0000
1:24331613:G:GG	donor_gain	1.0000
1:24331613:GT:G	donor_loss	1.0000
1:24331614:T:G	donor_loss	1.0000
1:24334641:TCAG:T	acceptor_loss	1.0000
1:24334643:A:AG	acceptor_gain	1.0000
1:24334643:A:C	acceptor_loss	1.0000
1:24334643:AG:A	acceptor_gain	1.0000
1:24334644:G:GG	acceptor_gain	1.0000
1:24334644:G:GT	acceptor_loss	1.0000
1:24334644:GG:G	acceptor_gain	1.0000
1:24334701:A:T	donor_gain	1.0000
1:24334702:AAGAG:A	donor_loss	1.0000
1:24334703:AGAGG:A	donor_loss	1.0000
1:24334704:GAG:G	donor_gain	1.0000
1:24334705:AGG:A	donor_loss	1.0000
1:24334706:GGTGA:G	donor_loss	1.0000
1:24334707:GT:G	donor_loss	1.0000
1:24334708:T:A	donor_loss	1.0000
1:24336478:CCA:C	acceptor_loss	1.0000
1:24336479:CAGGT:C	acceptor_loss	1.0000
1:24336480:A:AG	acceptor_gain	1.0000
1:24336480:A:T	acceptor_loss	1.0000
1:24336480:AG:A	acceptor_gain	1.0000
1:24336481:G:GA	acceptor_gain	1.0000
1:24336481:GG:G	acceptor_gain	1.0000
1:24336481:GGT:G	acceptor_gain	1.0000

AlphaMissense

3984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:24331536:C:A	A43D	1.000
1:24337707:T:C	L253P	1.000
1:24337709:A:G	N254D	1.000
1:24337711:C:A	N254K	1.000
1:24337711:C:G	N254K	1.000
1:24337712:A:G	K255E	1.000
1:24337713:A:T	K255I	1.000
1:24337714:A:C	K255N	1.000
1:24337714:A:T	K255N	1.000
1:24337721:T:C	F258L	1.000
1:24337723:C:A	F258L	1.000
1:24337723:C:G	F258L	1.000
1:24337992:A:C	S281R	1.000
1:24337994:T:A	S281R	1.000
1:24337994:T:G	S281R	1.000
1:24338010:T:C	F287L	1.000
1:24338012:C:A	F287L	1.000
1:24338012:C:G	F287L	1.000
1:24338049:T:A	W300R	1.000
1:24338049:T:C	W300R	1.000
1:24338058:T:A	W303R	1.000
1:24338058:T:C	W303R	1.000
1:24339723:T:A	N336K	1.000
1:24339723:T:G	N336K	1.000
1:24339724:G:C	A337P	1.000
1:24339739:T:A	W342R	1.000
1:24339739:T:C	W342R	1.000
1:24342137:T:C	L357P	1.000
1:24342139:A:C	S358R	1.000
1:24342140:G:T	S358I	1.000

dbSNP variants (sampled 300 via entrez): RS1000024751 (1:24357255 G>A), RS1000031255 (1:24332293 C>G,T), RS1000083479 (1:24351098 C>T), RS1000307223 (1:24343970 G>A,C,T), RS1000354744 (1:24357064 A>G), RS1000442167 (1:24339283 T>C), RS1000450222 (1:24352789 G>A), RS1000569366 (1:24346121 C>A), RS1000641147 (1:24344548 C>T), RS1000677860 (1:24362607 G>A,C), RS1000691774 (1:24356835 C>G,T), RS1000774086 (1:24340745 T>A,C), RS1000912732 (1:24345626 C>A), RS1000965739 (1:24327815 T>C), RS1000983726 (1:24333949 C>T)

Disease associations

OMIM: gene MIM:608317 | disease phenotypes: MIM:606713, MIM:119540, MIM:119300, MIM:105650

GenCC curated gene-disease

Disease	Classification	Inheritance
van der Woude syndrome 2	Definitive	Autosomal dominant
GRHL3-related orofacial clefting	Definitive	Autosomal dominant
van der Woude syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
GRHL3-related orofacial clefting	Definitive	AD

Mondo (6): van der Woude syndrome 2 (MONDO:0011712), isolated cleft palate (MONDO:0007336), van der Woude syndrome (MONDO:0019508), Diamond-Blackfan anemia (MONDO:0015253), van der Woude syndrome 1 (MONDO:0007333), GRHL3-related orofacial clefting (MONDO:0100579)

Orphanet (3): Van der Woude syndrome (Orphanet:888), Cleft palate (Orphanet:2014), Diamond-Blackfan anemia (Orphanet:124)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000163	Abnormal oral cavity morphology
HP:0000175	Cleft palate
HP:0000185	Cleft soft palate
HP:0000193	Bifid uvula
HP:0000196	Lower lip pit
HP:0000204	Cleft upper lip
HP:0000220	Velopharyngeal insufficiency
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000668	Hypodontia
HP:0000674	Anodontia
HP:0000689	Dental malocclusion
HP:0001611	Hypernasal speech
HP:0002033	Poor suck
HP:0002463	Language impairment
HP:0002870	Obstructive sleep apnea
HP:0003577	Congenital onset
HP:0008376	Nasal dysarthria
HP:0008872	Feeding difficulties in infancy
HP:0009088	Speech articulation difficulties
HP:0010286	Abnormal salivary gland morphology
HP:0010296	Ankyloglossia
HP:0010863	Receptive language delay
HP:0011219	Short face
HP:0011469	Nasal regurgitation
HP:0011819	Submucous cleft soft palate
HP:0011951	Aspiration pneumonia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001526_20	Fasting blood insulin (BMI interaction)	6.000000e-06
GCST003193_1	Response to interferon beta in multiple sclerosis	6.000000e-06
GCST005946_1	Cleft palate	3.000000e-08
GCST005946_2	Cleft palate	4.000000e-09
GCST005947_1	Cleft palate	7.000000e-08
GCST005947_2	Cleft palate	1.000000e-07
GCST005947_6	Cleft palate	7.000000e-08
GCST006661_57	Male-pattern baldness	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D029503	Anemia, Diamond-Blackfan	C15.378.050.085.080.090; C15.378.050.750.500; C15.378.190.223.500.500.090; C16.320.077.090
C536528	Van der Woude syndrome (supp.)
C536529	Van der Woude syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, affects cotreatment	6
trichostatin A	affects cotreatment, increases expression	3
Formaldehyde	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression	2
Vorinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases mutagenesis	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
lead acetate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Leflunomide	increases expression	1
Arsenic	decreases expression, increases abundance	1

Clinical trials (associated diseases)

41 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00673608	PHASE4	COMPLETED	Magnetic Resonance Imaging (MRI) Assessments of the Heart and Liver Iron Load in Patients With Transfusion Induced Iron Overload
NCT00235391	PHASE3	COMPLETED	Expanded Access of Deferasirox to Patients With Congenital Disorders of Red Blood Cells and Chronic Iron Overload
NCT00001962	PHASE2	TERMINATED	A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure
NCT00011505	PHASE2	COMPLETED	Mobilization of Stem Cells With G-CSF for Collection From Patients With Diamond-Blackfan Anemia
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00957931	PHASE2	COMPLETED	Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT02386267	PHASE2	UNKNOWN	L-leucine in Diamond Blackfan Anemia Patients
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04099966	PHASE2	RECRUITING	AlloSCT for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT03392701	Not specified	COMPLETED	Possible Links Between Inflammation and Lipid Metabolism
NCT05850221	Not specified	COMPLETED	Anaerobic Exercise and Mental Acuity
NCT06437405	Not specified	COMPLETED	Resistance Exercise Plus Vinegar Ingestion on Biomarkers in Healthy Adults
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00176878	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT01362595	PHASE1/PHASE2	COMPLETED	Pilot Phase I/II Study of Amino Acid Leucine in Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia
NCT01419704	PHASE1/PHASE2	WITHDRAWN	Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
NCT01464164	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Study of Sotatercept in Adults With Transfusion Dependent Diamond Blackfan Anemia
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT02065869	PHASE1/PHASE2	TERMINATED	Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03653338	PHASE1/PHASE2	RECRUITING	T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
NCT03733249	PHASE1/PHASE2	TERMINATED	Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study
NCT03966053	PHASE1/PHASE2	TERMINATED	The Use of Trifluoperazine in Transfusion Dependent DBA
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00244010	Not specified	COMPLETED	Partially Matched Stem Cell Transplantation for Patients With Refractory Severe Aplastic Anemia or Refractory Cytopenias
NCT00290628	Not specified	TERMINATED	Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer
NCT01114776	Not specified	COMPLETED	Multi-Center Study of Iron Overload: Pilot Study
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT01758042	Not specified	COMPLETED	Bone Marrow and Kidney Transplant for Patients With Chronic Kidney Disease and Blood Disorders
NCT01913548	Not specified	COMPLETED	Multi-Center Study of Iron Overload: Survey Study (MCSIO)
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening