GRHL3

Chr 1AD

grainyhead like transcription factor 3

Also known as: SOM, TFCP2L4, VWS2

NCBI Gene: 57822 ENSG00000158055 UniProt: Q8TE85 OMIM: 608317

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.[provided by RefSeq, Aug 2010]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.281 OMIM phenotype

Clinical Summary— GRHL3

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Gene-Disease Validity (ClinGen)

GRHL3-related orofacial clefting · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 130 VUS of 272 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GRHL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.993

Z-score 4.38

OE 0.11 (0.05–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.42Z-score

OE missense 0.79 (0.71–0.87)

284 obs / 359.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.28)

0≤0.351.4

Missense OE?0.79 (0.71–0.87)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 3 / 28.0Missense obs/exp: 284 / 359.9Syn Z: 0.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGRHL3-related Van der Woude syndromeLOFAD

This gene — mechanism propensity

0.3594th %ile

GOF

0.3193th %ile

LOF

0.78top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 75% of P/LP variants are LoF · LOEUF 0.28

DN1 literature citation

Literature Evidence

DNA subset of van der Woude cases is caused by dominant-negative mutations in the epithelial transcription factor Grainyhead like-3 (GRHL3), and Grhl3-/-mice have soft-tissue syndactyly.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32109382 ↗

ClinVar Variant Classifications

272 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic8

VUS130

Likely Benign41

Benign60

Conflicting9

Pathogenic

Likely Pathogenic

130

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	2	0	0	12
Likely Pathogenic	5	3	0	0	8
VUS	2	125	2	1	130
Likely Benign	0	13	10	18	41
Benign	0	13	38	9	60
Conflicting	—				9
Total	17	156	50	28	260

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

5 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap GRHL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →