Familial hemophagocytic lymphohistiocytosis: genes and variants
Familial hemophagocytic lymphohistiocytosis is linked to 4 analyzed proteins (UNC13D, CDC42, SLC2A10 and COL3A1). 8 DNA variants are known to cause it; 449 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Familial hemophagocytic lymphohistiocytosis 3; familial hemophagocytic lymphohistiocytosis type 1
Genes linked to Familial hemophagocytic lymphohistiocytosis
UNC13D: Protein unc-13 homolog D
It primes cytotoxic granules for membrane fusion in natural-killer cells and cytotoxic T cells, enabling release of perforin and granzymes. Biallelic loss-of-function variants cause familial hemophagocytic lymphohistiocytosis type 3 with uncontrolled immune activation.
7 disease-causing and 449 uncertain variants in UNC13D are linked to Familial hemophagocytic lymphohistiocytosis.
CDC42: Cell division control protein 42 homolog
It acts as a molecular switch controlling actin organization, cell polarity, migration, vesicle trafficking, and multiple developmental signaling pathways. Germline dysregulating variants can cause Takenouchi-Kosaki syndrome and related neurodevelopmental disorders with hematologic and immune abnormalities.
1 disease-causing and 0 uncertain variants in CDC42 are linked to Familial hemophagocytic lymphohistiocytosis.
SLC2A10: Solute carrier family 2, facilitated glucose transporter member 10
0 disease-causing and 0 uncertain variants in SLC2A10 are linked to Familial hemophagocytic lymphohistiocytosis.
COL3A1: Collagen alpha-1(III) chain
Its type III collagen fibrils provide tensile support in arteries, bowel, uterus, skin, and other distensible connective tissues. Pathogenic variants cause vascular Ehlers-Danlos syndrome with marked arterial and hollow-organ fragility.
0 disease-causing and 0 uncertain variants in COL3A1 are linked to Familial hemophagocytic lymphohistiocytosis.
Weakly linked (only a few uncertain records): ACTA2, TGFBR1, FHL1, MYH11 and TGFB2.
Where Familial hemophagocytic lymphohistiocytosis variants cluster
- UNC13D Interaction with RAB27A (positions 240–543): 3 of 7 disease-causing changes, 1.5× more than its size predicts.
Known disease-causing variants in Familial hemophagocytic lymphohistiocytosis
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| UNC13D R414C | 414 | Interaction with RAB27A | Disease-causing (★★) |
| UNC13D R414L | 414 | Interaction with RAB27A | Disease-causing (★★) |
| UNC13D A1018D | 1018 | C2 2 | Disease-causing (★★) |
| CDC42 R186C | 186 | Disease-causing (★★) | |
| UNC13D E616G | 616 | MHD1 | Disease-causing (★★) |
| UNC13D L1058P | 1058 | Disease-causing (★) | |
| UNC13D L403P | 403 | Interaction with RAB27A | Disease-causing (★) |
| UNC13D F857C | 857 | MHD2 | Disease-causing |
Same protein, different disease
- Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome is also caused by CDC42 variants; they fall mostly in different places as the Familial hemophagocytic lymphohistiocytosis variants (6 disease-causing).
Diseases related to Familial hemophagocytic lymphohistiocytosis
- Familial thoracic aortic aneurysm and aortic dissection, also linked to COL3A1 and SLC2A10
- Familial aortopathy, also linked to COL3A1 and SLC2A10
- Ehlers-Danlos syndrome, also linked to COL3A1
- Connective tissue disorder, also linked to COL3A1
- Autoinflammatory syndrome, also linked to UNC13D
- Arterial tortuosity syndrome, also linked to SLC2A10
- Fetal anomalies with a likely genetic cause, also linked to CDC42
- Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, also linked to COL3A1
- Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, also linked to CDC42
- Thoracic aortic aneurysm or dissection, also linked to SLC2A10
Frequently asked questions
Which genes are linked to Familial hemophagocytic lymphohistiocytosis?
In CATVariant, Familial hemophagocytic lymphohistiocytosis is linked to 4 analyzed proteins: UNC13D (Protein unc-13 homolog D), CDC42 (Cell division control protein 42 homolog), SLC2A10 (Solute carrier family 2, facilitated glucose transporter member 10) and COL3A1 (Collagen alpha-1(III) chain).
How many genetic variants are linked to Familial hemophagocytic lymphohistiocytosis?
528 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 449 are of uncertain significance or have conflicting reports.
Which uncertain variants in Familial hemophagocytic lymphohistiocytosis look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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