HSF5

Summary

HSF5 (heat shock transcription factor 5, HGNC:26862) is a protein-coding gene on chromosome 17q22, encoding Heat shock factor protein 5 (Q4G112). DNA-binding transcription factor that is essential for male fertility, spermatogenesis and meiotic prophase progression in spermatocytes under non-stress conditions.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in several processes, including male meiotic nuclear division; regulation of DNA-templated transcription; and spermatogenesis. Predicted to be located in XY body and nucleus.

Source: NCBI Gene 124535 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 54 total — 1 pathogenic
• MANE Select transcript: NM_001080439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26862
Approved symbol	HSF5
Name	heat shock transcription factor 5
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	FLJ40311
Ensembl gene	ENSG00000176160
Ensembl biotype	protein_coding
OMIM	620843
Entrez	124535

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000323777

RefSeq mRNA: 1 — MANE Select: NM_001080439 NM_001080439

CCDS: CCDS32690

Canonical transcript exons

ENST00000323777 — 6 exons

Exon	Start	End
ENSE00001226426	58458768	58458945
ENSE00001226434	58462782	58463303
ENSE00001226446	58466885	58466979
ENSE00001293235	58487725	58488408
ENSE00001304964	58420167	58422430
ENSE00001312635	58479893	58480267

Expression profiles

Bgee: expression breadth broad, 34 present calls, max score 96.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2008 / max 186.2981, expressed in 4 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167271	0.1952	4
167270	0.0057	3

Top tissues by expression

247 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	96.24	gold quality
adult organism	UBERON:0007023	94.86	gold quality
secondary oocyte	CL:0000655	91.97	gold quality
oocyte	CL:0000023	87.30	gold quality
left testis	UBERON:0004533	86.60	gold quality
right testis	UBERON:0004534	85.95	gold quality
testis	UBERON:0000473	85.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.13	gold quality
pancreatic ductal cell	CL:0002079	65.55	silver quality
lymph node	UBERON:0000029	58.95	gold quality
bone marrow cell	CL:0002092	56.78	gold quality
epithelial cell of pancreas	CL:0000083	55.32	gold quality
vermiform appendix	UBERON:0001154	54.86	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
bone marrow	UBERON:0002371	53.61	silver quality
upper arm skin	UBERON:0004263	53.52	gold quality
tibialis anterior	UBERON:0001385	53.49	silver quality
caecum	UBERON:0001153	51.59	gold quality
granulocyte	CL:0000094	51.02	silver quality
myocardium	UBERON:0002349	50.25	gold quality
deltoid	UBERON:0001476	50.23	gold quality
thymus	UBERON:0002370	49.31	silver quality
blood	UBERON:0000178	49.19	silver quality
cerebellar vermis	UBERON:0004720	48.93	gold quality
tonsil	UBERON:0002372	48.49	gold quality
quadriceps femoris	UBERON:0001377	47.05	gold quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.69

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA2676.1	HSF5	HSF factors

JASPAR matrix evidence (PMIDs): PMID:38684656

miRNA regulators (miRDB)

142 targeting HSF5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-9902	99.89	69.15	2250

Literature-anchored findings (GeneRIF, showing 1)

• Heat shock factor 5 correlated with immune infiltration serves as a prognostic biomarker in lung adenocarcinoma. (PMID:33390814)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hsf5	ENSMUSG00000070345
rattus_norvegicus	Hsf5	ENSRNOG00000056793
drosophila_melanogaster	Hsf	FBGN0001222
caenorhabditis_elegans	hsf-1	WBGENE00002004

Paralogs (9): HSF2 (ENSG00000025156), HSF4 (ENSG00000102878), HSFY2 (ENSG00000169953), HSFX1 (ENSG00000171116), HSFY1 (ENSG00000172468), HSF1 (ENSG00000185122), HSFX2 (ENSG00000268738), HSFX4 (ENSG00000283463), HSFX3 (ENSG00000283697)

Protein

Protein identifiers

Heat shock factor protein 5 — Q4G112 (reviewed: Q4G112)

Alternative names: Heat shock transcription factor 5

All UniProt accessions (1): Q4G112

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding transcription factor that is essential for male fertility, spermatogenesis and meiotic prophase progression in spermatocytes under non-stress conditions. Positvely and negatively regulates gene expression to ensure progression of meiotic prophase beyond pachytene stage in spermatocytes.

Subunit / interactions. Homooligomer.

Subcellular location. Nucleus. Chromosome.

Similarity. Belongs to the HSF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q4G112-1	1	yes
Q4G112-2	2

RefSeq proteins (1): NP_001073908* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000232	HSF_DNA-bd	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00447

UniProt features (7 total): sequence variant 2, chain 1, DNA-binding region 1, region of interest 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8ZYS	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4G112-F1	53.53	0.13

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 572

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 96 (showing top): GOBP_MALE_GAMETE_GENERATION, GOBP_ORGANELLE_FISSION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, chr17q22, GOBP_MEIOTIC_CELL_CYCLE, GOCC_SEX_CHROMOSOME, GOCC_XY_BODY, GOBP_CELL_CYCLE_PROCESS, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_NPC_HCP_WITH_H3_UNMETHYLATED, MEISSNER_BRAIN_HCP_WITH_H3_UNMETHYLATED, MIKKELSEN_MEF_HCP_WITH_H3_UNMETHYLATED, GOBP_MALE_MEIOTIC_NUCLEAR_DIVISION

GO Biological Process (7): male meiotic nuclear division (GO:0007140), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), meiotic cell cycle (GO:0051321)

GO Molecular Function (6): DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription repressor activity (GO:0001217), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): XY body (GO:0001741), nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	3
regulation of DNA-templated transcription	3
transcription cis-regulatory region binding	3
male gamete generation	2
meiotic nuclear division	2
DNA-binding transcription factor activity	2
meiotic cell cycle	1
developmental process involved in reproduction	1
cellular developmental process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
positive regulation of DNA-templated transcription	1
negative regulation of DNA-templated transcription	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
DNA binding	1
sex chromosome	1
condensed chromatin of inactivated sex chromosome	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

542 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSF5	HRC	P23327	570
HSF5	YBX2	Q9Y2T7	431
HSF5	DNAJB1	P25685	426
HSF5	HSPB7	Q9UBY9	426
HSF5	C5orf58	C9J3I9	418
HSF5	HYOU1	Q9Y4L1	387
HSF5	CCER2	I3L3R5	357
HSF5	GTSF1L	Q9H1H1	338
HSF5	CCSER1	Q9C0I3	335
HSF5	HSPA4	P34932	333
HSF5	HEATR9	A2RTY3	323
HSF5	DENND2D	Q9H6A0	322
HSF5	MPZL3	Q6UWV2	321
HSF5	TINAG	Q9UJW2	318
HSF5	HSPB8	Q9UJY1	317
HSF5	B0YIZ1	B0YIZ1	317

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CCL8	HSF5	psi-mi:“MI:0915”(physical association)	0.370
ARMC9	PRMT5	psi-mi:“MI:0914”(association)	0.350
HSF5	ACTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): HSF5 (Affinity Capture-MS), HSF5 (Positive Genetic), HSF5 (Affinity Capture-MS), HSF5 (Affinity Capture-MS), ACTN1 (Affinity Capture-Luminescence), SAMHD1 (Affinity Capture-Luminescence), ACTN1 (Affinity Capture-MS), SAMHD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTS1, A0A1B0GWH4, A1A4L6, A1YGI6, A6NDR6, B8QB46, F1MJR8, F1QDF8, O35892, O35893, P09015, P15036, P15037, P23497, P52729, P59598, Q32NH9, Q3KRF1, Q3UM89, Q4G112, Q4V7E1, Q5M7N6, Q5ND04, Q5XIV2, Q5ZHX5, Q66IG8, Q6P1R3, Q6PCX9, Q6PJQ5, Q708W2, Q76I76, Q76I79, Q76N89, Q7M6U3, Q8AXQ4, Q8BVK9, Q8IUE0, Q8IUE1, Q8IWB6, Q8IXJ9

Diamond homologs: A0A1B0GTS1, A0A1B0GWH4, B7XIV9, C4V6H6, D0VYS2, G0SB31, G5EFT5, J9VHZ9, O14283, O49403, P10961, P22121, P22335, P22813, P38529, P38530, P38531, P38532, P38533, P41151, P41153, P41154, Q00613, Q02953, Q03933, Q08DJ8, Q10PR4, Q1HGE8, Q1PDN3, Q338B0, Q40152, Q4G112, Q5A4X5, Q5AQ33, Q5CZP2, Q5KMX8, Q5ND04, Q652B0, Q67TP9, Q6F388

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

54 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	48
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
394267	GRCh37/hg19 17q22(chr17:52189051-57477162)x3	Pathogenic

SpliceAI

1203 predictions. Top by Δscore:

Variant	Effect	Δscore
17:58422431:C:CC	acceptor_gain	0.9900
17:58458778:T:A	donor_gain	0.9900
17:58466977:CAG:C	acceptor_gain	0.9900
17:58466978:AG:A	acceptor_gain	0.9900
17:58466979:GCTG:G	acceptor_loss	0.9900
17:58466980:C:CC	acceptor_gain	0.9900
17:58466980:CT:C	acceptor_loss	0.9900
17:58469697:A:AC	donor_gain	0.9900
17:58469698:G:C	donor_gain	0.9900
17:58422376:T:TA	donor_gain	0.9800
17:58458945:CCTA:C	acceptor_loss	0.9800
17:58458947:TAAAA:T	acceptor_loss	0.9800
17:58462807:T:TA	donor_gain	0.9800
17:58462820:C:CT	donor_gain	0.9800
17:58462821:T:TT	donor_gain	0.9800
17:58463881:CAT:C	donor_gain	0.9800
17:58466878:ATCTT:A	donor_loss	0.9800
17:58466879:TCTTA:T	donor_loss	0.9800
17:58466880:CTTA:C	donor_loss	0.9800
17:58466881:TTAC:T	donor_loss	0.9800
17:58466882:TA:T	donor_loss	0.9800
17:58466883:ACCTG:A	donor_loss	0.9800
17:58466884:CCT:C	donor_loss	0.9800
17:58466975:CACAG:C	acceptor_gain	0.9800
17:58469743:T:A	donor_gain	0.9800
17:58480700:C:CT	acceptor_gain	0.9800
17:58487719:ACTC:A	donor_loss	0.9800
17:58487720:CT:C	donor_loss	0.9800
17:58487721:TCAC:T	donor_loss	0.9800
17:58487722:CAC:C	donor_loss	0.9800

AlphaMissense

3878 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:58488179:C:A	W32C	1.000
17:58488179:C:G	W32C	1.000
17:58488181:A:G	W32R	1.000
17:58488181:A:T	W32R	1.000
17:58487890:G:T	R129S	0.999
17:58487927:G:C	F116L	0.999
17:58487927:G:T	F116L	0.999
17:58487928:A:G	F116S	0.999
17:58487929:A:G	F116L	0.999
17:58487942:G:C	F111L	0.999
17:58487942:G:T	F111L	0.999
17:58487944:A:G	F111L	0.999
17:58488008:G:C	F89L	0.999
17:58488008:G:T	F89L	0.999
17:58488009:A:G	F89S	0.999
17:58488010:A:G	F89L	0.999
17:58488044:G:C	F77L	0.999
17:58488044:G:T	F77L	0.999
17:58488046:A:G	F77L	0.999
17:58488153:A:T	I41N	0.999
17:58488180:C:G	W32S	0.999
17:58488218:C:A	W19C	0.999
17:58488218:C:G	W19C	0.999
17:58488220:A:G	W19R	0.999
17:58488220:A:T	W19R	0.999
17:58488233:G:C	F14L	0.999
17:58488233:G:T	F14L	0.999
17:58488234:A:C	F14C	0.999
17:58488235:A:G	F14L	0.999
17:58487870:C:A	K135N	0.998

dbSNP variants (sampled 300 via entrez): RS1000020417 (17:58463544 A>C), RS1000050063 (17:58463919 A>G,T), RS1000073788 (17:58459921 C>A), RS1000077964 (17:58467643 T>C), RS1000129261 (17:58452671 G>A), RS1000184393 (17:58441693 G>A,T), RS1000195954 (17:58439980 AT>A,ATT), RS1000249271 (17:58452431 A>T), RS1000266089 (17:58444083 A>G), RS1000292963 (17:58443784 A>G), RS1000326996 (17:58474553 C>A,G), RS1000369170 (17:58430113 T>G), RS1000419366 (17:58437089 A>C), RS1000450352 (17:58436908 G>T), RS1000508178 (17:58458340 T>A)

Disease associations

OMIM: gene MIM:620843 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002602_6	Vitamin D levels	1.000000e-06
GCST002774_29	Cognitive function	3.000000e-07
GCST005316_215	Intelligence (MTAG)	6.000000e-09
GCST006269_1086	General cognitive ability	4.000000e-11
GCST010002_126	Refractive error	7.000000e-42

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Smoke	decreases expression	1
Zinc	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.