HBG2

Summary

HBG2 (hemoglobin subunit gamma 2, HGNC:4832) is a protein-coding gene on chromosome 11p15.4, encoding Hemoglobin subunit gamma-2 (P69892). Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.

The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. The order of the genes in the beta-globin cluster is: 5’- epsilon – gamma-G – gamma-A – delta – beta–3'.

Source: NCBI Gene 3048 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 69 total — 9 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• MANE Select transcript: NM_000184

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4832
Approved symbol	HBG2
Name	hemoglobin subunit gamma 2
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	HBG-T1
Ensembl gene	ENSG00000196565
Ensembl biotype	protein_coding
OMIM	142250
Entrez	3048

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000336906, ENST00000380252, ENST00000444587

RefSeq mRNA: 1 — MANE Select: NM_000184 NM_000184

CCDS: CCDS7755

Canonical transcript exons

ENST00000336906 — 3 exons

Exon	Start	End
ENSE00001701103	5254637	5254781
ENSE00003475901	5254292	5254514
ENSE00003849864	5253188	5253405

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 99.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.2110 / max 191.2229, expressed in 110 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118369	2.2110	110
118368	0.0829	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	99.94	gold quality
adrenal tissue	UBERON:0018303	99.87	gold quality
ganglionic eminence	UBERON:0004023	99.81	gold quality
ventricular zone	UBERON:0003053	99.48	gold quality
cortical plate	UBERON:0005343	98.60	gold quality
blood	UBERON:0000178	96.96	gold quality
monocyte	CL:0000576	94.86	gold quality
leukocyte	CL:0000738	92.47	gold quality
bone marrow	UBERON:0002371	84.99	gold quality
bone marrow cell	CL:0002092	76.81	gold quality
apex of heart	UBERON:0002098	74.97	gold quality
spleen	UBERON:0002106	73.49	gold quality
lung	UBERON:0002048	70.11	gold quality
upper lobe of left lung	UBERON:0008952	69.53	gold quality
gastrocnemius	UBERON:0001388	69.28	gold quality
heart left ventricle	UBERON:0002084	68.53	gold quality
right lobe of liver	UBERON:0001114	68.32	gold quality
amygdala	UBERON:0001876	68.28	gold quality
heart	UBERON:0000948	67.69	gold quality
temporal lobe	UBERON:0001871	67.68	gold quality
right adrenal gland cortex	UBERON:0035827	67.43	gold quality
right adrenal gland	UBERON:0001233	67.41	gold quality
right lung	UBERON:0002167	66.78	gold quality
popliteal artery	UBERON:0002250	66.53	gold quality
tibial artery	UBERON:0007610	66.51	gold quality
substantia nigra	UBERON:0002038	66.33	gold quality
Ammon’s horn	UBERON:0001954	66.31	gold quality
lower esophagus mucosa	UBERON:0035834	66.29	gold quality
muscle of leg	UBERON:0001383	66.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.45	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	424016.11
E-MTAB-7407	yes	367557.74
E-CURD-112	yes	340962.21
E-MTAB-8221	yes	313738.54
E-MTAB-10042	yes	305478.99
E-GEOD-124472	yes	304969.54
E-MTAB-8205	yes	286207.12
E-MTAB-8894	yes	269633.94
E-HCAD-10	yes	250324.03
E-MTAB-9067	yes	247438.32
E-MTAB-10662	yes	203674.18
E-HCAD-4	yes	187526.47
E-CURD-79	yes	166760.21
E-MTAB-6701	yes	163432.04
E-MTAB-9906	yes	139486.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL11A, CHD4, CREB1, CSF2, CTDSPL2, EIF2S1, GATA1, JUN, KLF11, KLF1, NFE2, SON, SOX6, YBX3, ZNF410

Literature-anchored findings (GeneRIF, showing 40)

• Assembly of human hemoglobin (Hb) beta- and gamma-globin chains expressed in a cell-free system with alpha-globin chains to form Hb A and Hb F. (PMID:11827978)
• in an Albanian family, two mutations of the gamma-globin promoter (for both HBG1 and HBG2) are assoicated in trans with a beta thal point mutation, that results in increased levels of HbF (PMID:14649320)
• Data show that (G)Gamma-158(C–>T) had a strong association with moderately increased Hb F levels in beta-thalassemia heterozygotes in the Guangxi area of China. (PMID:15476181)
• 3’ flank of the Ggamma-globin gene contains multiple weak pause elements which, combined with the strong polyA signal the gene possesses, are likely to cause gradual termination across the 3’ flank. (PMID:15798211)
• A determinant linked to the XmnI restriction site which effects Ggamma-globin gene expression (and Hemoglobin F production) is active in beta-Thalassemic (anemic) adults but not in normal infants. (PMID:17365007)
• This work describes the study of the interactions of different hemoglobin variants HbA, HbE and HbF and the globin subunits of HbA with the two aminophospholipids in the presence and absence of cholesterol. (PMID:17916326)
• study reports 2 new forms of nondeletional hereditary persistence of fetal hemoglobin; the presence of a (G)gamma-196 C–>T in the first case and an (A)gamma-201 C–>T in the second was revealed (PMID:18096417)
• These results suggest that the GATA motif under study has a functional role in silencing gamma-globin gene expression in adults. (PMID:18443038)
• analysis of heme uptake from human methemoglobin by the iron-regulated surface determinants system of Staphylococcus aureus (PMID:18467329)
• HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the hereditary persistence of fetal hemoglobin phenotype observed in our index cases (PMID:19050890)
• Data suggest the G gamma-globin promoter is activated by cJun via an upstream cAMP response element. (PMID:19861239)
• No statistically significant difference in the frequency of positive XmnI(G)gamma polymorphism was observed between thalassemia intermedia and thalassemia major patients. (PMID:19892574)
• A G>C substitution at position 479 of the (G)gamma-globin gene results in a glutamic acid to glutamine substitution at codon 101 of the (G)gamma-globin chain, a new gamma chain variant that we have named Hb F-Zhejiang (PMID:20113294)
• role of the hematopoietic transcription factor GATA-1, its cofactor FOG-1, and the associated chromatin remodeling complex NuRD in the developmental silencing of HBG1 and HBG2 gene expression (PMID:20439494)
• The polymorphisms -396_-391 del HBG2, -369 SNP HBG2 and -271 SNP HBG1 correlated with HbF levels, hence, it suggests an important role of HBG2 and HBG1 gene polymorphisms on the HbF synthesis. (PMID:20602015)
• The recently identified chromatin factor Friend of Prmt1 (FOP) is a critical modulator of gamma-globin gene expression. (PMID:20688955)
• 12 molecules in the unit cell describe a right-handed helical filament having no polarity, which is different from the filament composed of HbS fibers, which is the only other well characterized fiber of human hemoglobin (PMID:21123872)
• We identified a missense mutation in the fetal Ggamma-globin gene (HBG2) in a father and daughter with transient neonatal cyanosis and anemia. (PMID:21561349)
• Chromatin looping between the Ggamma-globin gene and LCR HSs requires NF-E2. (PMID:21609963)
• although the prevalence of Xmn1-(G)gamma polymorphism is high in beta thalassemia intermedia patients, it alone could not predict clinical severity of disease (PMID:21755589)
• results establish SATB2 as a novel gamma-globin gene regulator and provide a glimpse of the differential and cooperative roles of SATB family proteins in modulating clustered genes transcription (PMID:22825848)
• the study demonstrated that Egyptian beta-thalessemia patients have low frequency of positivity for the Xmnl polymorphism whether in heterozygous (+/-) or homozygous (+/+) state (PMID:22871617)
• Our data suggest that a temporal repression mechanism is operative in the silencing of gamma-globin gene expression (PMID:23284307)
• Hb F is regulated in inherited bone marrow failure syndromes by Xmn1-HBG2, as it is in the haemoglobinopathies. (PMID:23713742)
• Data suggest that segregation of BCL11A haplotype 2 indicating an involvement of this locus in Hb F expression. (PMID:23777413)
• Its polymorphism effects HbF, HbE, MCV and MCH levels in Thai HbE carriers. (PMID:24474642)
• Data indicate that the T to A conversion results in a leucine to histidine amino acid change at codon 105 of the (G)gamma-globin HBG2 gene and caused a hemoglobin (Hb) variant with lowered oxygen affinity. (PMID:24502349)
• DNA polymorphisms at BCL11A, HBS1L-MYB and Xmn1-HBG2 site loci associated with fetal hemoglobin levels in sickle cell anemia patients from Northern Brazil. (PMID:25084696)
• Hemoglobin gamma G plays a role in modifying clinical symptoms of beta-thalassemia innorthern Thailand. (PMID:25123009)
• In Portuguese beta-thalassemia carriers the HBG2 XmnI polymorphism is strongly associated with HbF levels. (PMID:25842369)
• The frequency of rs7482144 was determined in Colombian sickle cell anemia patients. It indicated a West African ethnic background. (PMID:26849705)
• Genetic association studies provide a rationale for functional studies of HBG2 expression in wild-type and T/A/T haplotype erythroblasts and mechanistic studies like chromatin conformation capture experiments, to evaluate the role of chromatin looping as a mediator of the T/A/T haplotype effects on HbF. (PMID:27185208)
• The results suggested that there was a significant relationship between high fetal hemoglobin levels and two variations (-309A/T and -369C/G) in Ggamma gene promotor. (PMID:29412791)
• Some forms of hereditary persistence of fetal hemoglobin, a rare benign condition where individuals express the gamma-globin gene throughout adulthood, are caused by point mutations in the gamma-globin gene promoter at regions residing ~115 and 200 bp upstream of the transcription start site. We found that the major fetal globin gene repressors BCL11A and ZBTB7A directly bound to the sites at -115 and -200 bp, respecti… (PMID:29610478)
• Data suggest that studying genotype frequency of the Xmn1 gammaG globin polymorphism (-158C>T ) in Siwa Oasis, Egypt can be considered as a starting point for further research targeting this community sector. (PMID:29932071)
• Prx2 interacts with hemoglobin A (Alpha2Beta2) and hemoglobin F (Alpha2Gamma2) but not with hemoglobin A2 (Alpha2Delta2) (PMID:30844732)
• Multi-Locus Models to Address Hb F Variability in Portuguese beta-Thalassemia Carriers. (PMID:32319326)
• XmnI Polymorphism in Sickle Cell Disease in North Morocco. (PMID:32508152)
• Thalassemia Major and Intermedia Patients in East Java do not Show Fetal Hemoglobin Level Difference in Relation to XMNI Polymorphism. (PMID:32577047)
• Association between BCL11A, HSB1L-MYB, and XmnI gammaG-158 (C/T) gene polymorphism and hemoglobin F level in Egyptian sickle cell disease patients. (PMID:32772141)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	hbae5	ENSDARG00000045142
danio_rerio	hbaa2	ENSDARG00000069735
danio_rerio	si:ch211-5k11.8	ENSDARG00000079078
danio_rerio	hbae3	ENSDARG00000079305
danio_rerio	hbae1.2	ENSDARG00000088330
danio_rerio	hbae1.3	ENSDARG00000089124
danio_rerio	hbae1.1	ENSDARG00000089475
danio_rerio	hbaa1	ENSDARG00000097011
drosophila_melanogaster	glob1	FBGN0027657
caenorhabditis_elegans		WBGENE00008996
caenorhabditis_elegans		WBGENE00077763

Paralogs (11): HBQ1 (ENSG00000086506), HBZ (ENSG00000130656), CYGB (ENSG00000161544), HBA2 (ENSG00000188536), MB (ENSG00000198125), HBA1 (ENSG00000206172), HBM (ENSG00000206177), HBE1 (ENSG00000213931), HBG1 (ENSG00000213934), HBD (ENSG00000223609), HBB (ENSG00000244734)

Protein

Protein identifiers

Hemoglobin subunit gamma-2 — P69892 (reviewed: P69892)

Alternative names: Gamma-2-globin, Hb F Ggamma, Hemoglobin gamma-2 chain, Hemoglobin gamma-G chain

All UniProt accessions (4): A0A0J9YYA3, P69892, D9YZU9, E9PBW4

UniProt curated annotations — full annotation on UniProt →

Function. Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.

Subunit / interactions. Heterotetramer of two alpha chains and two gamma chains in fetal hemoglobin (Hb F).

Tissue specificity. Red blood cells.

Post-translational modifications. Acetylation of Gly-2 converts Hb F to the minor Hb F1.

Disease relevance. Cyanosis transient neonatal (TNCY) [MIM:613977] A disorder characterized by cyanosis in the fetus and neonate, due to a defect in the fetal hemoglobin chain which has reduced affinity for oxygen. Some patients develop anemia resulting from increased destruction of red cells containing abnormal or unstable hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months of age or earlier, as the adult beta-globin chain is produced and replaces the fetal gamma-globin chain. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the globin family.

RefSeq proteins (1): NP_000175* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000971	Globin	Domain
IPR002337	Hemoglobin_b	Family
IPR009050	Globin-like_sf	Homologous_superfamily
IPR012292	Globin/Proto	Homologous_superfamily
IPR050056	Hemoglobin_oxygen_transport	Family

Pfam: PF00042

UniProt features (75 total): sequence variant 49, modified residue 11, helix 10, binding site 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7QU4	X-RAY DIFFRACTION	1.66
4MQJ	X-RAY DIFFRACTION	1.8
4MQK	X-RAY DIFFRACTION	2.24
1FDH	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P69892-F1	97.14	0.98

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 (2): 64 (distal binding residue); 93 (proximal binding residue)

Post-translational modifications (11): 60, 83, 94, 140, 143, 144, 2, 13, 45, 51, 53

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 149 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_ERYTHROCYTE_HOMEOSTASIS, TANG_SENESCENCE_TP53_TARGETS_UP, GOBP_ONE_CARBON_COMPOUND_TRANSPORT, GOBP_GAS_TRANSPORT, DELYS_THYROID_CANCER_DN, GOBP_OXYGEN_TRANSPORT, MAGRANGEAS_MULTIPLE_MYELOMA_IGLL_VS_IGLK_UP, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, HAN_SATB1_TARGETS_DN, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOMF_OXYGEN_BINDING, GOBP_ERYTHROCYTE_DEVELOPMENT

GO Biological Process (3): carbon dioxide transport (GO:0015670), oxygen transport (GO:0015671), erythrocyte development (GO:0048821)

GO Molecular Function (6): oxygen carrier activity (GO:0005344), oxygen binding (GO:0019825), heme binding (GO:0020037), hemoglobin alpha binding (GO:0031721), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (4): cytosol (GO:0005829), hemoglobin complex (GO:0005833), haptoglobin-hemoglobin complex (GO:0031838), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gas transport	2
cellular anatomical structure	2
protein-containing complex	2
one-carbon compound transport	1
erythrocyte differentiation	1
myeloid cell development	1
oxygen transport	1
oxygen binding	1
molecular carrier activity	1
small molecule binding	1
tetrapyrrole binding	1
hemoglobin binding	1
cation binding	1
binding	1
cytoplasm	1
cytosol	1
extracellular region	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

38 interactions, top by confidence:

A	B	Type	Score
HBZ	HBB	psi-mi:“MI:0915”(physical association)	0.860
HBG2	HBA1	psi-mi:“MI:0915”(physical association)	0.680
HBA1	HBG2	psi-mi:“MI:0407”(direct interaction)	0.680
HBG2	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.560
HBG2	HBM	psi-mi:“MI:0915”(physical association)	0.560
HBQ1	HBG2	psi-mi:“MI:0915”(physical association)	0.560
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
HBG1	HBG2	psi-mi:“MI:0915”(physical association)	0.400
HBZ	HBG1	psi-mi:“MI:0915”(physical association)	0.400
HBG2	RPSA	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	HBG2	psi-mi:“MI:0915”(physical association)	0.370
HBG2	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370
HBG2	RAP1BL	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
VCAM1		psi-mi:“MI:0914”(association)	0.350
AGGF1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
LARP7	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
QKI	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
RPS11	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
U2AF1	MED19	psi-mi:“MI:2364”(proximity)	0.270
ZNF800	MED19	psi-mi:“MI:2364”(proximity)	0.270
ZRANB2	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
TRIM54	HBG2	psi-mi:“MI:0915”(physical association)	0.000
HBG2	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.000
HBG2	HBA1	psi-mi:“MI:0915”(physical association)	0.000
HBM	HBG2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): HBG2 (Affinity Capture-MS), HBG2 (Affinity Capture-MS), HBG2 (Two-hybrid), HBG2 (Two-hybrid), HBG2 (Two-hybrid), HBA1 (Two-hybrid), HBM (Two-hybrid), UBB (Affinity Capture-MS), GNAZ (Affinity Capture-MS), TTC19 (Affinity Capture-MS), CADM4 (Affinity Capture-MS), CCNY (Affinity Capture-MS), RAP1BL (Affinity Capture-MS), SRC (Affinity Capture-MS), HRAS (Affinity Capture-MS)

ESM2 similar proteins: O77655, P02097, P02103, P02125, P06643, P08224, P08225, P11342, P15165, P18994, P18995, P19760, P29626, P51438, P51440, P51441, P51442, P61920, P61921, P62741, P62742, P68016, P68017, P68018, P68019, P68020, P68021, P68022, P68023, P68024, P68025, P68028, P68029, P68061, P68062, P68063, P68077, P68078, P68079, P69892

Diamond homologs: B3EWR8, C0HJT6, C0HJT7, K7N5M6, O09232, O13077, O13078, O13163, O13164, O93348, O93349, O93351, P02097, P02112, P02114, P02115, P02116, P02121, P02124, P02125, P02139, P02140, P02141, P02142, P04443, P07406, P08851, P0C0U8, P0C239, P0C240, P10058, P10782, P11025, P11342, P11749, P14521, P16309, P16418, P18995, P23017

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
BCL11A	“down-regulates quantity by repression”	HBG2	“transcriptional regulation”
CSF2	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
CTDSPL2	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
GATA1	“down-regulates quantity by repression”	HBG2	“transcriptional regulation”
SOX6	“down-regulates quantity by repression”	HBG2	“transcriptional regulation”
EIF2S1	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
KLF11	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
NFE2	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
oxygen transport	6	217.9×	3e-11
erythrocyte development	6	109.0×	2e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	3
Uncertain significance	15
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
14982	NC_000011.10:g.5254983G>C	Pathogenic
14983	NC_000011.10:g.5254956A>G	Pathogenic
14989	NM_000184.2(HBG2):c.277C>T (p.His93Tyr)	Pathogenic
14990	NC_000011.10:g.5254895G>A	Pathogenic
15001	NC_000011.10:g.5254895G>T	Pathogenic
29752	NM_000184.3(HBG2):c.191A>T (p.His64Leu)	Pathogenic
29754	NC_000011.10:g.5255348A>C	Pathogenic
563883	GRCh37/hg19 11p15.5-15.1(chr11:230615-17099213)x3	Pathogenic
800493	NM_000184.3(HBG2):c.85C>A (p.Leu29Met)	Pathogenic
14981	NM_000184.3(HBG2):c.190C>T (p.His64Tyr)	Likely pathogenic
29753	NM_000184.3(HBG2):c.202G>A (p.Val68Met)	Likely pathogenic
423096	NM_000184.3(HBG2):c.151TCTGCC[3] (p.51SA[3])	Likely pathogenic

SpliceAI

5612 predictions. Top by Δscore:

Variant	Effect	Δscore
11:5253545:T:A	donor_gain	1.0000
11:5254287:CTCA:C	donor_loss	1.0000
11:5254288:TCAC:T	donor_loss	1.0000
11:5254289:CACCT:C	donor_loss	1.0000
11:5254290:A:AC	donor_gain	1.0000
11:5254290:AC:A	donor_gain	1.0000
11:5254290:ACCTT:A	donor_loss	1.0000
11:5254291:C:CC	donor_gain	1.0000
11:5254291:CC:C	donor_gain	1.0000
11:5254510:GGAGC:G	acceptor_gain	1.0000
11:5254513:GC:G	acceptor_gain	1.0000
11:5254513:GCCT:G	acceptor_loss	1.0000
11:5254514:CC:C	acceptor_gain	1.0000
11:5254515:C:CC	acceptor_gain	1.0000
11:5254523:T:C	acceptor_gain	1.0000
11:5254523:T:TC	acceptor_gain	1.0000
11:5268471:A:AC	donor_gain	1.0000
11:5268481:A:AC	donor_gain	1.0000
11:5268481:ATGGG:A	donor_gain	1.0000
11:5268482:T:C	donor_gain	1.0000
11:5269450:TCA:T	donor_loss	1.0000
11:5269451:CACCT:C	donor_loss	1.0000
11:5269452:A:AC	donor_gain	1.0000
11:5269452:A:AT	donor_loss	1.0000
11:5269453:C:CC	donor_gain	1.0000
11:5269453:C:CG	donor_loss	1.0000
11:5269453:C:CT	donor_loss	1.0000
11:5269677:C:CC	acceptor_gain	1.0000
11:5269679:A:C	acceptor_gain	1.0000
11:5253403:GAGC:G	acceptor_loss	0.9900

AlphaMissense

962 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:5254295:G:C	F104L	0.997
11:5254295:G:T	F104L	0.997
11:5254297:A:G	F104L	0.997
11:5254478:A:C	F43L	0.996
11:5254478:A:T	F43L	0.996
11:5254480:A:G	F43L	0.996
11:5254469:A:C	F46L	0.993
11:5254469:A:T	F46L	0.993
11:5254471:A:G	F46L	0.993
11:5254330:G:C	H93D	0.991
11:5254296:A:G	F104S	0.990
11:5254298:G:C	N103K	0.990
11:5254298:G:T	N103K	0.990
11:5254413:C:A	G65V	0.990
11:5254413:C:T	G65D	0.990
11:5254425:A:T	V61D	0.989
11:5253330:A:G	W131R	0.988
11:5253330:A:T	W131R	0.988
11:5254328:G:C	H93Q	0.987
11:5254328:G:T	H93Q	0.987
11:5254330:G:T	H93N	0.985
11:5254417:G:C	H64D	0.985
11:5254479:A:G	F43S	0.985
11:5254481:G:C	F42L	0.985
11:5254481:G:T	F42L	0.985
11:5254483:A:G	F42L	0.985
11:5254296:A:C	F104C	0.984
11:5254480:A:T	F43I	0.984
11:5254433:G:C	N58K	0.981
11:5254433:G:T	N58K	0.981

dbSNP variants (sampled 300 via entrez): RS1000612522 (11:5255070 C>A), RS1002165377 (11:5256278 G>T), RS1009030264 (11:5255966 T>G), RS1009083246 (11:5256371 G>A), RS1009661108 (11:5256302 A>G), RS1009954919 (11:5256143 A>G), RS1010847232 (11:5252726 G>A), RS1012390984 (11:5253654 G>A), RS1012506797 (11:5255020 A>G), RS10128653 (11:5256231 A>C,G), RS1014069466 (11:5255780 T>A,G), RS1014184030 (11:5255981 G>A,C), RS1016159633 (11:5255352 C>G,T), RS1017576072 (11:5256558 C>T), RS1020467346 (11:5255802 C>A,T)

Disease associations

OMIM: gene MIM:142250 | disease phenotypes: MIM:613977

GenCC curated gene-disease

Disease	Classification	Inheritance
cyanosis, transient neonatal	Strong	Autosomal dominant
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	Strong	Autosomal dominant
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome	Supportive	Autosomal recessive
hemoglobinopathy Toms River	Supportive	Autosomal dominant

Mondo (5): cyanosis, transient neonatal (MONDO:0013511), hereditary persistence of fetal hemoglobin (MONDO:0020989), hereditary persistence of fetal hemoglobin-sickle cell disease syndrome (MONDO:0016672), hemoglobinopathy Toms River (MONDO:0017238), hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome (MONDO:0018749)

Orphanet (1): Low oxygen affinity gamma chain hemoglobin disease (Orphanet:280615)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000488	Retinopathy
HP:0000952	Jaundice
HP:0000961	Cyanosis
HP:0000980	Pallor
HP:0001744	Splenomegaly
HP:0001746	Asplenia
HP:0001903	Anemia
HP:0001923	Reticulocytosis
HP:0002027	Abdominal pain
HP:0002113	Pulmonary infiltrates
HP:0002240	Hepatomegaly
HP:0002829	Arthralgia
HP:0003330	Abnormal bone structure
HP:0003577	Congenital onset
HP:0004840	Hypochromic microcytic anemia
HP:0008346	Increased red cell sickling tendency
HP:0011904	Persistence of hemoglobin F
HP:0012119	Methemoglobinemia
HP:0032169	Severe infection
HP:0034336	Splenic infarction
HP:0045047	HbS hemoglobin

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000532_1	Beta thalassemia/hemoglobin E disease	3.000000e-15
GCST003122_3	Hemoglobin levels	4.000000e-86
GCST003122_7	Hemoglobin levels	1.000000e-25
GCST004329_7	Mean corpuscular hemoglobin concentration	4.000000e-07
GCST004536_1	Hemoglobin	5.000000e-11
GCST004621_21	Red cell distribution width	7.000000e-12
GCST007005_5	Logical memory (immediate recall) in normal cognition	3.000000e-06
GCST007006_9	Logical memory (delayed recall) in normal cognition	1.000000e-07
GCST008863_4	Malate levels	8.000000e-07
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55
GCST90002385_189	High light scatter reticulocyte count	4.000000e-10
GCST90002386_415	High light scatter reticulocyte percentage of red cells	3.000000e-09
GCST90002391_237	Mean corpuscular hemoglobin concentration	1.000000e-12
GCST90002392_558	Mean corpuscular volume	4.000000e-09
GCST90002396_454	Mean reticulocyte volume	2.000000e-24
GCST90002396_455	Mean reticulocyte volume	3.000000e-09
GCST90002397_560	Mean spheric corpuscular volume	7.000000e-24
GCST90002397_561	Mean spheric corpuscular volume	2.000000e-13
GCST90002403_238	Red blood cell count	2.000000e-12
GCST90002404_506	Red cell distribution width	2.000000e-43
GCST90002405_271	Reticulocyte count	4.000000e-13
GCST90002406_358	Reticulocyte fraction of red cells	5.000000e-12

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0005845	hemoglobin A2 measurement
EFO:0004576	fetal hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0009188	Red cell distribution width
EFO:0004874	memory performance
EFO:0010508	malate measurement
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067217 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7482144	HBG2		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.73	Kd	1856	nM	CHEMBL5653589
5.58	ED50	2660	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148488: Binding affinity to human HBG2 incubated for 45 mins by Kinobead based pull down assay	kd	1.8564	uM

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
tetrabromobisphenol A	decreases expression	1
hydroquinone	affects binding, increases reaction	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
thiamet G	affects binding, increases reaction, decreases expression	1
Resveratrol	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Aspirin	increases expression	1
Benzo(a)pyrene	affects methylation	1
Ditiocarb	increases expression, increases reaction	1
Disulfiram	increases expression, increases reaction	1
Doxorubicin	increases expression, increases stability	1
Fluoxetine	decreases reaction, increases expression	1
Primaquine	affects response to substance, increases expression, increases reaction, decreases reaction	1
Progesterone	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Thiotepa	decreases reaction, increases expression	1
Troleandomycin	decreases reaction, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression	1
Cyclosporine	increases expression	1
Butyric Acid	increases expression	1
alpha-Tocopherol	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651530	Binding	Binding affinity to human HBG2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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