GRHL2

Chr 8ADAR

grainyhead like transcription factor 2

Also known as: BOM, DFNA28, ECTDS, PPCD4, TFCP2L3

NCBI Gene: 79977 ENSG00000083307 UniProt: Q6ISB3 OMIM: 608576

This gene encodes a transcription factor that binds to specific DNA sequences to regulate epithelial development, primary neurulation, and expression of tight junction proteins including claudins. Mutations cause autosomal dominant non-syndromic sensorineural deafness (DFNA28), posterior polymorphous corneal dystrophy type 4, and autosomal recessive ectodermal dysplasia with short stature. The pathogenic mechanism involves loss of function, as the protein is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with either GRHL1 or GRHL3. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28).[provided by RefSeq, Mar 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.273 OMIM phenotypes

Clinical Summary— GRHL2

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · 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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 141 VUS of 345 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GRHL2

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?

0.27LOEUF

pLI 0.997

Z-score 5.04

OE 0.13 (0.07–0.27)

Highly constrained

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

Missense Constraint?

1.93Z-score

OE missense 0.71 (0.64–0.79)

246 obs / 347.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.27)

0≤0.351.4

Missense OE?0.71 (0.64–0.79)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 5 / 39.0Missense obs/exp: 246 / 347.0Syn Z: -1.27

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGRHL2-related posterior polymorphous corneal dystrophyOTHERAD

strongGRHL2-related ectodermal dysplasia and short stature syndromeOTHERAR

This gene — mechanism propensity

0.3793th %ile

GOF

0.2895th %ile

LOF

0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 82% of P/LP variants are LoF · LOEUF 0.27

Literature Evidence

LOFHaploinsufficiency of the GRHL2 gene contained within the microdeletion is proposed as a candidate genetic mechanism for this patient's hearing loss.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 26455667 ↗

ClinVar Variant Classifications

345 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic15

VUS141

Likely Benign101

Benign51

Conflicting8

Pathogenic

Likely Pathogenic

141

VUS

101

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	1	0	0	13
Likely Pathogenic	11	1	3	0	15
VUS	1	132	7	1	141
Likely Benign	0	4	60	37	101
Benign	0	2	44	5	51
Conflicting	—				8
Total	24	140	114	43	329

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap GRHL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →