Hemophagocytic lymphohistiocytosis, familial, 6

Summary

Hemophagocytic lymphohistiocytosis, familial, 6 (MONDO:0033557) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hemophagocytic lymphohistiocytosis, familial, 6
Mondo ID	MONDO:0033557
OMIM	618998
UMLS	C5436563
MedGen	1736944
GARD	0016400
Is cancer (heuristic)	no

Also known as: FHL6 · immune dysregulation and systemic hyperinflammation syndrome

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › hereditary hemophagocytic lymphohistiocytosis › hemophagocytic lymphohistiocytosis, familial, 6

Related subtypes (10): Chediak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis type 1, familial hemophagocytic lymphohistiocytosis 4, familial hemophagocytic lymphohistiocytosis 2, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, familial hemophagocytic lymphohistiocytosis 3, familial hemophagocytic lymphohistiocytosis 5, Hermansky-Pudlak syndrome 9, hemophagocytic lymphohistiocytosis due to RhoG deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
977475	NM_172071.4(RC3H1):c.2062C>T (p.Arg688Ter)	RC3H1	Pathogenic	no assertion criteria provided
2500075	NM_172071.4(RC3H1):c.437T>C (p.Val146Ala)	RC3H1	Uncertain significance	criteria provided, single submitter
3024391	NM_172071.4(RC3H1):c.71C>T (p.Thr24Ile)	RC3H1	Uncertain significance	criteria provided, single submitter
4293752	NM_172071.4(RC3H1):c.1778A>T (p.Tyr593Phe)	RC3H1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RC3H1	Moderate	Autosomal recessive	hemophagocytic lymphohistiocytosis, familial, 6	3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RC3H1	HGNC:29434	ENSG00000135870	Q5TC82	Roquin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RC3H1	Roquin-1	Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3’-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RC3H1	Transcription factor	no		Znf_CCCH, Znf_RING, Znf_RING/FYVE/PHD

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
tibialis anterior	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RC3H1	260	ubiquitous	marker	tibialis anterior, upper leg skin, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RC3H1	3,135

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RC3H1	Q5TC82	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of T-helper cell differentiation	1	16852.0×	8e-04	RC3H1
regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	16852.0×	8e-04	RC3H1
negative regulation of germinal center formation	1	8426.0×	0.001	RC3H1
regulation of miRNA metabolic process	1	5617.3×	0.001	RC3H1
regulation of T cell receptor signaling pathway	1	4213.0×	0.001	RC3H1
regulation of germinal center formation	1	2808.7×	0.002	RC3H1
negative regulation of T-helper 17 cell differentiation	1	1872.4×	0.002	RC3H1
T follicular helper cell differentiation	1	1404.3×	0.002	RC3H1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	1053.2×	0.002	RC3H1
P-body assembly	1	1053.2×	0.002	RC3H1
negative regulation of activated T cell proliferation	1	1053.2×	0.002	RC3H1
negative regulation of B cell proliferation	1	936.2×	0.002	RC3H1
lymph node development	1	802.5×	0.002	RC3H1
nuclear-transcribed mRNA catabolic process	1	766.0×	0.002	RC3H1
3’-UTR-mediated mRNA destabilization	1	766.0×	0.002	RC3H1
post-transcriptional regulation of gene expression	1	648.1×	0.003	RC3H1
B cell homeostasis	1	561.7×	0.003	RC3H1
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	468.1×	0.003	RC3H1
T cell homeostasis	1	455.5×	0.003	RC3H1
regulation of mRNA stability	1	421.3×	0.003	RC3H1
spleen development	1	401.2×	0.003	RC3H1
T cell proliferation	1	383.0×	0.003	RC3H1
cellular response to interleukin-1	1	280.9×	0.004	RC3H1
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.004	RC3H1
T cell receptor signaling pathway	1	151.8×	0.007	RC3H1
protein polyubiquitination	1	115.4×	0.009	RC3H1
ubiquitin-dependent protein catabolic process	1	74.2×	0.013	RC3H1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RC3H1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RC3H1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RC3H1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.