FHL3

Chr 1AR

four and a half LIM domains 3

Also known as: SLIM2

NCBI Gene: 2275ENSG00000183386UniProt: Q13643

The protein encoded by this gene is a member of a family of proteins containing a four-and-a-half LIM domain, which is a highly conserved double zinc finger motif. The encoded protein has been shown to interact with the cancer developmental regulators SMAD2, SMAD3, and SMAD4, the skeletal muscle myogenesis protein MyoD, and the high-affinity IgE beta chain regulator MZF-1. This protein may be involved in tumor suppression, repression of MyoD expression, and repression of IgE receptor expression. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

Hemophagocytic lymphohistiocytosis, familial, 3MIM #608898
AR
61
ClinVar variants
5
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— FHL3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 44 VUS of 61 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.84LOEUF
pLI 0.002
Z-score 2.01
OE 0.45 (0.26–0.84)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.79Z-score
OE missense 0.84 (0.73–0.95)
153 obs / 183.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.45 (0.26–0.84)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.73–0.95)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 7 / 15.6Missense obs/exp: 153 / 183.2Syn Z: 0.35

ClinVar Variant Classifications

61 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic1
VUS44
Likely Benign5
Benign1
4
Pathogenic
1
Likely Pathogenic
44
VUS
5
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
1
0
1
VUS
0
41
3
0
44
Likely Benign
0
1
1
3
5
Benign
0
1
0
0
1
Total0439355

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

View in ClinVar →

Protein Context — Lollipop Plot

FHL3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Hemophagocytic lymphohistiocytosis, familial, 3

MIM #608898

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Senescent fibroblasts secrete CTHRC1 to promote cancer stemness in hepatocellular carcinoma.
Huang H et al.·Cell Commun Signal
2025
Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review.
Amirifar P et al.·Pediatr Allergy Immunol
2021Review
AMBP protects against aortic valve calcification by inhibiting ERK1/2 and JNK pathways mediated by FHL3.
Guo C et al.·Theranostics
2025
The Hippo-YAP signaling pathway promotes hepatocellular carcinoma progression by inducing FHL3 expression.
Rao D et al.·Cell Death Dis
2025
Towards the Identification of Biomarkers for Muscle Function Improvement in Myotonic Dystrophy Type 1.
Aoussim A et al.·J Neuromuscul Dis
2023Review
Angeborene hämophagozytische Lymphohistiozytose (HLH).
Pachlopnik Schmid J et al.·Klin Padiatr
2010Review
Clinical and genetic features of UNC13D deficiency with hypogammaglobulinemia.
Xiong L et al.·Front Immunol
2025
FHL3 promotes pancreatic cancer invasion and metastasis through preventing the ubiquitination degradation of EMT associated transcription factors.
Li P et al.·Aging (Albany NY)
2020
Atypical familial hemophagocytic lymphohistiocytosis type 3 in children: A report of cases and literature review.
Zhao Q et al.·Pediatr Allergy Immunol
2024Review
[Analysis of clinical phenotype and genetic variant in a case of familial hemophagocytic lymphohistiocytosis type Ⅲ].
Wang Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2022Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3)

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

NOT YET RECRUITING
NCT06736080Phase PHASE1, PHASE2Assistance Publique - Hôpitaux de ParisStarted 2025-01
MUNC-CD34MUNC-T3

External Resources

Links to major genomics databases and tools