RC3H1

Chr 1AR

ring finger and CCCH-type domains 1

Also known as: FHL6, IMDSHY, RNF198, ROQUIN

NCBI Gene: 149041 ENSG00000135870 UniProt: Q5TC82 OMIM: 609424

RC3H1 encodes a post-transcriptional repressor that binds to specific RNA motifs in mRNA 3'-UTRs to promote mRNA degradation, particularly targeting inflammatory genes like TNF and ICOS, and also functions as a ubiquitin E3 ligase. Autosomal recessive mutations cause immune dysregulation and systemic hyperinflammation syndrome. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.29), indicating that complete loss of RC3H1 function is poorly tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein containing RING-type and C3H1-type zinc finger motifs. The encoded protein recognizes and binds to a constitutive decay element (CDE) in the 3' UTR of mRNAs, leading to mRNA deadenylation and degradation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.291 OMIM phenotype

Clinical Summary— RC3H1

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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

4 unique Pathogenic / Likely Pathogenic· 105 VUS of 137 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.993

Z-score 6.28

OE 0.18 (0.11–0.29)

Highly constrained

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

Missense Constraint?

2.79Z-score

OE missense 0.69 (0.63–0.74)

431 obs / 628.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.18 (0.11–0.29)

0≤0.351.4

Missense OE?0.69 (0.63–0.74)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 12 / 67.7Missense obs/exp: 431 / 628.1Syn Z: 1.59

This gene — mechanism propensity

0.3494th %ile

GOF

0.3788th %ile

LOF

0.74top 10%

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

LOFprediction above median · LOEUF 0.29

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

ClinVar Variant Classifications

137 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS105

Likely Benign7

Pathogenic

105

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	3	0	4
Likely Pathogenic	0	0	0	0	0
VUS	0	105	0	0	105
Likely Benign	0	4	1	2	7
Benign	0	0	0	0	0
Total	1	109	4	2	116

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 54) ClinVar copy-number / structural variants overlap RC3H1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →