Familial hemophagocytic lymphohistiocytosis 3

Summary

Familial hemophagocytic lymphohistiocytosis 3 (MONDO:0012146) is a disease caused by UNC13D (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: UNC13D (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,634
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hemophagocytic lymphohistiocytosis 3
Mondo ID	MONDO:0012146
MeSH	C537251
OMIM	608898
DOID	DOID:0110923
UMLS	C1837174
MedGen	332383
GARD	0009928
Is cancer (heuristic)	no

Also known as: familial hemophagocytic lymphohistiocytosis type 3 · FHL3 · genetic hemophagocytic lymphohistiocytosis caused by mutation in UNC13D · hemophagocytic lymphohistiocytosis, familial, 3 · hemophagocytic lymphohistiocytosis, familial, type 3 · HLH3 · HPLH3 · UNC13D genetic hemophagocytic lymphohistiocytosis

Data availability: 1,634 ClinVar variants · 4 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 › familial hemophagocytic lymphohistiocytosis 3

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 5, Hermansky-Pudlak syndrome 9, hemophagocytic lymphohistiocytosis, familial, 6, 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

600 retrieved; paginated sample, class counts are floors:

268 uncertain significance, 254 likely benign, 35 pathogenic, 17 conflicting classifications of pathogenicity, 13 benign, 8 pathogenic/likely pathogenic, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1349251	NM_199242.3(UNC13D):c.2709+2T>A	LOC112533672	Pathogenic	criteria provided, multiple submitters, no conflicts
1420143	NM_199242.3(UNC13D):c.2851C>T (p.Gln951Ter)	LOC112533672	Pathogenic	criteria provided, single submitter
2018314	NM_199242.3(UNC13D):c.2716dup (p.Thr906fs)	LOC112533672	Pathogenic	criteria provided, single submitter
2131281	NM_199242.3(UNC13D):c.2704C>T (p.Gln902Ter)	LOC112533672	Pathogenic	criteria provided, single submitter
1068466	NM_199242.3(UNC13D):c.2258_2259insA (p.His754fs)	UNC13D	Pathogenic	criteria provided, single submitter
1068528	NM_199242.3(UNC13D):c.82_83insCTCT (p.Asp28fs)	UNC13D	Pathogenic	criteria provided, single submitter
1070748	NM_199242.3(UNC13D):c.1055+1G>A	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070830	NM_199242.3(UNC13D):c.3018C>G (p.Tyr1006Ter)	UNC13D	Pathogenic	criteria provided, single submitter
1073330	NM_199242.3(UNC13D):c.1792C>T (p.Gln598Ter)	UNC13D	Pathogenic	criteria provided, single submitter
1074647	NM_199242.3(UNC13D):c.779G>A (p.Trp260Ter)	UNC13D	Pathogenic	criteria provided, single submitter
1074705	NM_199242.3(UNC13D):c.2037_2038insG (p.Arg680fs)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1074706	NM_199242.3(UNC13D):c.177_178del (p.Tyr61fs)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1074707	NM_199242.3(UNC13D):c.1545-2A>G	UNC13D	Pathogenic	criteria provided, single submitter
1076211	NM_199242.3(UNC13D):c.883C>T (p.Gln295Ter)	UNC13D	Pathogenic	criteria provided, single submitter
1299415	NM_199242.3(UNC13D):c.118-307G>A	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1299416	NM_199242.3(UNC13D):c.754-1G>C	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1323739	NM_199242.3(UNC13D):c.2381del (p.Leu794fs)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1333524	NM_199242.3(UNC13D):c.751C>T (p.Gln251Ter)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1338637	NM_199242.3(UNC13D):c.79dup (p.Arg27fs)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1400833	NM_199242.3(UNC13D):c.817C>T (p.Arg273Ter)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1411105	NM_199242.3(UNC13D):c.1807G>T (p.Glu603Ter)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1412812	NM_199242.3(UNC13D):c.859del (p.Arg287fs)	UNC13D	Pathogenic	criteria provided, single submitter
1454697	NM_199242.3(UNC13D):c.640C>T (p.Arg214Ter)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1455802	NM_199242.3(UNC13D):c.322-2A>T	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455815	NM_199242.3(UNC13D):c.1072dup (p.Ser358fs)	UNC13D	Pathogenic	criteria provided, single submitter
1687358	NM_199242.3(UNC13D):c.1612C>T (p.Gln538Ter)	UNC13D	Pathogenic	criteria provided, single submitter
1694203	NM_199242.3(UNC13D):c.1229_1230dup (p.Arg411fs)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1694217	NM_199242.3(UNC13D):c.570-2A>T	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810215	NM_199242.3(UNC13D):c.3053C>A (p.Ala1018Asp)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1996	NM_199242.3(UNC13D):c.1828_1839del (p.Arg610_Gln613del)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
UNC13D	Definitive	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UNC13D	Orphanet:540	Familial hemophagocytic lymphohistiocytosis

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
UNC13D	HGNC:23147	ENSG00000092929	Q70J99	Protein unc-13 homolog D	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UNC13D	Protein unc-13 homolog D	Plays a role in cytotoxic granule exocytosis in lymphocytes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UNC13D	Other/Unknown	no		C2_dom, MUN_dom, Munc13_1

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
bone marrow cell	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UNC13D	195	ubiquitous	marker	granulocyte, bone marrow cell, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UNC13D	907

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UNC13D	Q70J99	1

Function

Pathway analysis

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

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neutrophil degranulation	1	23.1×	0.043	UNC13D

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
granuloma formation	1	5617.3×	1e-03	UNC13D
positive regulation of regulated secretory pathway	1	3370.4×	1e-03	UNC13D
natural killer cell degranulation	1	2407.4×	1e-03	UNC13D
secretion	1	2106.5×	1e-03	UNC13D
regulation of mast cell degranulation	1	1872.4×	1e-03	UNC13D
germinal center formation	1	1685.2×	1e-03	UNC13D
positive regulation of exocytosis	1	601.9×	0.002	UNC13D
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.003	UNC13D
phagocytosis	1	240.7×	0.005	UNC13D
defense response to virus	1	69.3×	0.014	UNC13D

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
UNC13D	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	UNC13D

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)
UNC13D	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06736080	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of Gene Therapy of FHL Type 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA