FHL5

Chr 6AR

four and a half LIM domains 5

Also known as: 1700027G07Rik, ACT, FHL-5, dJ393D12.2

NCBI Gene: 9457ENSG00000112214UniProt: Q5TD97

The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene. Polymorphisms in this gene may be associated with susceptibility for migraine headaches. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Apr 2016]

Primary Disease Associations & Inheritance

Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion diseaseMIM #613101
AR
65
ClinVar variants
16
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— FHL5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 49 VUS of 65 total submissions

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.
1.61LOEUF
pLI 0.000
Z-score -0.14
OE 1.04 (0.69–1.61)
Tolerant

Highly tolerant — LoF variants common in population

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.
-0.31Z-score
OE missense 1.07 (0.94–1.22)
161 obs / 150.2 exp
Tolerant

Tolerant to missense variation

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.1.04 (0.69–1.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.94–1.22)
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.0.92
0≤1.21.6
LoF obs/exp: 14 / 13.4Missense obs/exp: 161 / 150.2Syn Z: 0.43

ClinVar Variant Classifications

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic1
VUS49
15
Pathogenic
1
Likely Pathogenic
49
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
15
0
15
Likely Pathogenic
0
0
1
0
1
VUS
0
40
9
0
49
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total04025065

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

View in ClinVar →

Protein Context — Lollipop Plot

FHL5 · 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, 5, with or without microvillus inclusion disease

MIM #613101

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FHL5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.
Wong D et al.·Circ Res
2023Meta-analysis
Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery.
Wei S et al.·J Headache Pain
2025
Angeborene hämophagozytische Lymphohistiozytose (HLH).
Pachlopnik Schmid J et al.·Klin Padiatr
2010Review
Association of FHL5 and LPA genetic polymorphisms with diabetes mellitus risk: a case-control study.
Xu X et al.·Aging Male
2023
Prevalence of type 5 familial hemophagocytic lymphohistiocytosis in Korea and novel mutations in STXBP2.
Seo JY et al.·Clin Genet
2016
Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).
Pagel J et al.·Blood
2012Cohort
Exploring the Association of Migraine Susceptibility SNPs With the Risk of Chronic Migraine.
Cargnin S et al.·Eur J Pain
2025
Clinical and Genetic Analysis of Nine Suspected Familial Haemophagocytic Lymphohistiocytosis Patients for MUNC13-4 Deficiency and Introducing Four Novel Mutations in UNC13D.
Vahidi M et al.·Iran J Allergy Asthma Immunol
2019Cohort
Development of gene therapy with a cyclic adenosine monophosphate response element decoy oligodeoxynucleotide to prevent vascular intimal hyperplasia.
Uchida D et al.·J Vasc Surg
2020
Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.
Stepensky P et al.·Pediatr Blood Cancer
2013Cohort
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools