FRRS1

Summary

FRRS1 (ferric chelate reductase 1, HGNC:27622) is a protein-coding gene on chromosome 1p21.2, encoding Ferric reductase 1 (Q6ZNA5). Ferric reductase that reduces Fe(3+) to Fe(2+) and could play a role in iron import into cells.

Members of the cytochrome b561 (CYB561; MIM 600019) family, including FRRS1, reduce ferric to ferrous iron before its transport from the endosome to the cytoplasm (Vargas et al., 2003 [PubMed 14499595]).

Source: NCBI Gene 391059 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 99 total
• MANE Select transcript: NM_001361041

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27622
Approved symbol	FRRS1
Name	ferric chelate reductase 1
Location	1p21.2
Locus type	gene with protein product
Status	Approved
Aliases	SDR2
Ensembl gene	ENSG00000156869
Ensembl biotype	protein_coding
OMIM	611578
Entrez	391059

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000287474, ENST00000370176, ENST00000489209, ENST00000492943, ENST00000646001, ENST00000852116

RefSeq mRNA: 2 — MANE Select: NM_001361041 NM_001013660, NM_001361041

CCDS: CCDS30780, CCDS91007

Canonical transcript exons

ENST00000646001 — 17 exons

Exon	Start	End
ENSE00001028788	99738086	99738268
ENSE00001028790	99740793	99740940
ENSE00001067082	99717410	99717525
ENSE00001067083	99719534	99719647
ENSE00001067089	99728493	99728640
ENSE00001167676	99742179	99742273
ENSE00001167685	99747294	99747430
ENSE00001312396	99729650	99729748
ENSE00001768513	99748573	99748768
ENSE00001974441	99748897	99749001
ENSE00003536712	99715586	99715672
ENSE00003577059	99712418	99712515
ENSE00003605771	99712105	99712163
ENSE00003816219	99703970	99709120
ENSE00003823692	99766607	99766635
ENSE00003828763	99710806	99710949
ENSE00003830969	99709198	99709259

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 90.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5049 / max 61.8116, expressed in 1230 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13494	3.5049	1230

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	90.29	silver quality
liver	UBERON:0002107	88.03	gold quality
right lobe of liver	UBERON:0001114	86.43	gold quality
germinal epithelium of ovary	UBERON:0001304	83.27	gold quality
adrenal tissue	UBERON:0018303	82.69	gold quality
esophagus squamous epithelium	UBERON:0006920	82.04	gold quality
lower esophagus mucosa	UBERON:0035834	82.00	gold quality
skin of abdomen	UBERON:0001416	81.66	gold quality
colonic epithelium	UBERON:0000397	81.29	gold quality
skin of leg	UBERON:0001511	81.21	gold quality
esophagus mucosa	UBERON:0002469	81.20	gold quality
zone of skin	UBERON:0000014	80.96	gold quality
vagina	UBERON:0000996	79.98	gold quality
upper arm skin	UBERON:0004263	79.73	silver quality
ectocervix	UBERON:0012249	79.44	gold quality
corpus epididymis	UBERON:0004359	79.14	gold quality
gingival epithelium	UBERON:0001949	78.55	gold quality
gingiva	UBERON:0001828	78.28	gold quality
right adrenal gland	UBERON:0001233	77.55	gold quality
stromal cell of endometrium	CL:0002255	77.39	gold quality
upper leg skin	UBERON:0004262	76.95	gold quality
placenta	UBERON:0001987	76.85	gold quality
oral cavity	UBERON:0000167	76.83	gold quality
right adrenal gland cortex	UBERON:0035827	76.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.46	gold quality
left adrenal gland	UBERON:0001234	76.07	gold quality
uterine cervix	UBERON:0000002	75.98	gold quality
mucosa of transverse colon	UBERON:0004991	75.84	gold quality
adrenal gland	UBERON:0002369	75.62	gold quality
left adrenal gland cortex	UBERON:0035825	75.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.09
E-MTAB-9801	no	3.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting FRRS1, 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-3682-5P	99.93	67.97	1163
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-34C-3P	98.11	65.60	858
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-3667-5P	97.16	64.87	591
HSA-MIR-4761-3P	96.27	66.26	524
HSA-MIR-4509	96.19	65.80	900

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	frrs1a	ENSDARG00000076183
danio_rerio	frrs1b	ENSDARG00000077605
mus_musculus	Frrs1	ENSMUSG00000033386
rattus_norvegicus	Frrs1	ENSRNOG00000016351
drosophila_melanogaster	CG8399	FBGN0034067
drosophila_melanogaster	CG14515	FBGN0039648
drosophila_melanogaster	l(2)34Fc	FBGN0261534
caenorhabditis_elegans		WBGENE00007339
caenorhabditis_elegans		WBGENE00007545
caenorhabditis_elegans		WBGENE00013292
caenorhabditis_elegans		WBGENE00019746
caenorhabditis_elegans		WBGENE00077490

Paralogs (2): REELD1 (ENSG00000250673), FRRS1L (ENSG00000260230)

Protein

Protein identifiers

Ferric reductase 1 — Q6ZNA5 (reviewed: Q6ZNA5)

Alternative names: Ferric-chelate reductase 1, Stromal cell-derived receptor 2

All UniProt accessions (1): Q6ZNA5

UniProt curated annotations — full annotation on UniProt →

Function. Ferric reductase that reduces Fe(3+) to Fe(2+) and could play a role in iron import into cells. The electron donor and therefore the reaction mechanism are not known.

Subcellular location. Membrane.

Cofactor. Binds 2 heme b groups non-covalently.

Similarity. Belongs to the FRRS1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZNA5-1	1	yes
Q6ZNA5-2	2

RefSeq proteins (2): NP_001013682, NP_001347970* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002861	Reeler_dom	Domain
IPR005018	DOMON_domain	Domain
IPR006593	Cyt_b561/ferric_Rdtase_TM	Domain
IPR042307	Reeler_sf	Homologous_superfamily
IPR051237

Pfam: PF02014, PF03351

UniProt features (20 total): transmembrane region 7, binding site 4, domain 3, glycosylation site 3, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZNA5-F1	88.49	0.64

Functional residue map

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

Ligand- & substrate-binding residues (4): 373 (axial binding residue); 414 (axial binding residue); 446 (axial binding residue); 482 (axial binding residue)

Glycosylation sites (3): 138, 308, 321

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, LA_MEN1_TARGETS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GROSS_HYPOXIA_VIA_HIF1A_UP, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_MONOATOMIC_ION_HOMEOSTASIS, BASAKI_YBX1_TARGETS_DN, LANDIS_ERBB2_BREAST_PRENEOPLASTIC_UP, chr1p21, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_METAL_IONS, CHEN_METABOLIC_SYNDROM_NETWORK

GO Biological Process (1): intracellular iron ion homeostasis (GO:0006879)

GO Molecular Function (3): oxidoreductase activity, acting on metal ions (GO:0016722), metal ion binding (GO:0046872), oxidoreductase activity (GO:0016491)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
oxidoreductase activity	1
cation binding	1
catalytic activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

486 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRRS1	CYB561	P49447	956
FRRS1	HPX	P02790	774
FRRS1	CYB561D2	O14569	622
FRRS1	HSD17B14	Q9BPX1	507
FRRS1	CYBRD1	Q53TN4	507
FRRS1	CYB561A3	Q8NBI2	478
FRRS1	SPDYE2	Q495Y8	417
FRRS1	PALMD	Q9NP74	412
FRRS1	SPATA45	Q537H7	396
FRRS1	OR6K3	Q8NGY3	396
FRRS1	CD109	Q6YHK3	366
FRRS1	SLC11A2	P49281	358
FRRS1	ZNF841	Q6ZN19	352
FRRS1	SLC39A14	Q15043	348
FRRS1	PLPPR4	Q7Z2D5	323

IntAct

0 interactions, top by confidence:

BioGRID (2): FRRS1 (Proximity Label-MS), FRRS1 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2K1Q8, A2VE04, A4QP81, G5ECB2, O08680, O13146, O62714, O75899, O88871, O88917, O88923, O94910, O95490, O97817, O97827, O97831, P29319, P35384, P48442, P54755, P54757, P54758, Q07497, Q21540, Q5TZ24, Q5U9X3, Q61703, Q62413, Q6INU7, Q6ZNA5, Q7TT41, Q80T41, Q80TR1, Q80TS3, Q8BG22, Q8BXJ9, Q8C7U7, Q8JZZ7, Q8K385, Q8MSU3

Diamond homologs: A0A1B0GV85, A2VE04, P0C963, Q0Q028, Q0Q029, Q5MGQ0, Q6INU7, Q6ZNA5, Q765V4, Q86RS3, Q8K385, Q9V3Y3, A4QP81, B1AXV0, D3ZE85, P35446, P35447, Q8VCC9, Q9GLX9, Q9HCB6, Q9P0K9, Q9W770, Q008X1, O96382, Q8MSU3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2891 predictions. Top by Δscore:

Variant	Effect	Δscore
1:99709193:CTTA:C	donor_loss	1.0000
1:99709195:TA:T	donor_loss	1.0000
1:99709196:ACCTC:A	donor_loss	1.0000
1:99709255:TTCAA:T	acceptor_gain	1.0000
1:99709256:TCAA:T	acceptor_gain	1.0000
1:99709257:CAA:C	acceptor_gain	1.0000
1:99709257:CAAC:C	acceptor_gain	1.0000
1:99709258:AA:A	acceptor_gain	1.0000
1:99709258:AACT:A	acceptor_loss	1.0000
1:99709259:ACTG:A	acceptor_loss	1.0000
1:99709260:C:CC	acceptor_gain	1.0000
1:99709260:CT:C	acceptor_loss	1.0000
1:99709261:T:A	acceptor_loss	1.0000
1:99709264:C:CT	acceptor_gain	1.0000
1:99710835:T:TA	donor_gain	1.0000
1:99710945:TGCCA:T	acceptor_gain	1.0000
1:99710947:CCA:C	acceptor_gain	1.0000
1:99710948:CA:C	acceptor_gain	1.0000
1:99710948:CAC:C	acceptor_gain	1.0000
1:99710950:C:CC	acceptor_gain	1.0000
1:99710954:A:C	acceptor_gain	1.0000
1:99710957:C:CT	acceptor_gain	1.0000
1:99712161:CTT:C	acceptor_gain	1.0000
1:99712164:C:CC	acceptor_gain	1.0000
1:99712168:C:CT	acceptor_gain	1.0000
1:99712413:AGTAC:A	donor_loss	1.0000
1:99712414:GTA:G	donor_loss	1.0000
1:99712415:TA:T	donor_loss	1.0000
1:99712417:C:A	donor_loss	1.0000
1:99712514:TG:T	acceptor_gain	1.0000

AlphaMissense

3915 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:99710863:A:G	W523R	0.988
1:99710863:A:T	W523R	0.988
1:99717488:G:C	S386R	0.988
1:99717488:G:T	S386R	0.988
1:99717490:T:G	S386R	0.988
1:99742259:A:C	S116R	0.987
1:99742259:A:T	S116R	0.987
1:99742261:T:G	S116R	0.987
1:99747345:G:C	F94L	0.985
1:99747345:G:T	F94L	0.985
1:99747347:A:G	F94L	0.985
1:99742182:A:G	F142S	0.982
1:99747400:A:G	F76S	0.982
1:99728591:C:G	C303S	0.981
1:99728592:A:T	C303S	0.981
1:99747399:A:C	F76L	0.981
1:99747399:A:T	F76L	0.981
1:99747401:A:G	F76L	0.981
1:99728592:A:G	C303R	0.980
1:99747346:A:G	F94S	0.979
1:99742217:C:A	W130C	0.977
1:99742217:C:G	W130C	0.977
1:99717505:A:G	W381R	0.976
1:99717505:A:T	W381R	0.976
1:99740932:A:T	V146D	0.976
1:99742219:A:G	W130R	0.976
1:99742219:A:T	W130R	0.976
1:99747397:A:G	L77P	0.975
1:99717464:G:C	F394L	0.974
1:99717464:G:T	F394L	0.974

dbSNP variants (sampled 300 via entrez): RS1000008487 (1:99704658 G>A), RS1000050906 (1:99743115 T>A,C), RS1000095837 (1:99706668 T>G), RS1000106892 (1:99749524 T>C), RS1000130434 (1:99752609 T>C), RS1000151011 (1:99712339 T>C), RS1000152920 (1:99756700 A>G), RS1000207488 (1:99747165 T>C), RS1000210455 (1:99704974 G>A), RS1000221461 (1:99712823 G>A), RS1000359510 (1:99704842 G>C), RS1000403168 (1:99737804 A>G), RS1000469025 (1:99719096 G>A,C), RS1000553735 (1:99711232 T>A,C), RS1000566131 (1:99732601 T>C,G)

Disease associations

OMIM: gene MIM:611578 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001764_6	White matter integrity (bipolar disorder risk interaction)	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004641	white matter integrity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression	1
jinfukang	decreases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Naled	affects expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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