F8A2

Summary

F8A2 (coagulation factor VIII associated 2, HGNC:31849) is a protein-coding gene on chromosome Xq28, encoding 40-kDa huntingtin-associated protein (P23610). RAB5A effector molecule that is involved in vesicular trafficking of early endosomes.

This gene is part of a region that is repeated three times on chromosome X, once in intron 22 of the F8 gene and twice closer to the Xq telomere. This record represents the middle copy. Although its function is unknown, the observation that this gene is conserved in the mouse implies it has some function. Unlike factor VIII, this gene is transcribed abundantly in a wide variety of cell types.

Source: NCBI Gene 474383 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 3 total
• MANE Select transcript: NM_001007523

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31849
Approved symbol	F8A2
Name	coagulation factor VIII associated 2
Location	Xq28
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000288709
Ensembl biotype	protein_coding
Entrez	474383

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000369505

RefSeq mRNA: 1 — MANE Select: NM_001007523 NM_001007523

CCDS: CCDS35462

Canonical transcript exons

ENST00000369505 — 1 exons

Exon	Start	End
ENSE00001797540	155382095	155383801

Expression profiles

Top tissues by expression

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

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Thus these hydrophobic mutations at the A2 subunit interfaces result in high binding affinities for the A2 subunit and correlate well with previously observed reductions in rates in FVIIIa decay. (PMID:24899227)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	f8a	ENSDARG00000025518
mus_musculus	F8a	ENSMUSG00000078317
rattus_norvegicus	F8a1	ENSRNOG00000080664
rattus_norvegicus		ENSRNOG00000085632
drosophila_melanogaster	Hap40	FBGN0030671

Paralogs (2): F8A3 (ENSG00000277150), F8A1 (ENSG00000288722)

Protein

Protein identifiers

40-kDa huntingtin-associated protein — P23610 (reviewed: P23610)

Alternative names: CpG island protein, Factor VIII intron 22 protein

All UniProt accessions (1): P23610

UniProt curated annotations — full annotation on UniProt →

Function. RAB5A effector molecule that is involved in vesicular trafficking of early endosomes. Mediates the recruitment of HTT by RAB5A onto early endosomes. The HTT-F8A1/F8A2/F8A3-RAB5A complex stimulates early endosomal interaction with actin filaments and inhibits interaction with microtubules, leading to the reduction of endosome motility.

Subunit / interactions. Interacts with HTT (via C-terminus). Interacts with RAB5A. Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A onto early endosomes.

Subcellular location. Cytoplasm. Nucleus. Early endosome. Nuclear body.

Tissue specificity. Produced abundantly in a wide variety of cell types.

Disease relevance. Up-regulated in brain tissue from patients affected by Huntington’s disease (at protein level). In a Huntington’s disease mouse model overexpression of F8A1/F8A2/F8A3 impairs proteasome activity leading to the accumulation of mutant HTT and causes defective mitochondrial functions.

RefSeq proteins (1): NP_001007524* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR039494	F8A	Family

UniProt features (27 total): helix 13, turn 3, strand 3, compositionally biased region 2, initiator methionine 1, chain 1, region of interest 1, short sequence motif 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9PMW	ELECTRON MICROSCOPY	2.1
9PN0	ELECTRON MICROSCOPY	2.3
9YR6	ELECTRON MICROSCOPY	2.3
6X9O	ELECTRON MICROSCOPY	2.6
8VLX	ELECTRON MICROSCOPY	2.6
8W15	ELECTRON MICROSCOPY	2.72
8SAH	ELECTRON MICROSCOPY	3.2
7DXJ	ELECTRON MICROSCOPY	3.6
6EZ8	ELECTRON MICROSCOPY	4
7DXK	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23610-F1	78.88	0.42

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): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 29 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_VESICLE_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_VESICLE_CYTOSKELETAL_TRAFFICKING, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_ORGANELLE_LOCALIZATION, GOBP_REGULATION_OF_PROTEOLYSIS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CATABOLIC_PROCESS, GOCC_NUCLEAR_BODY, GOBP_PROTEOLYSIS

GO Biological Process (2): vesicle cytoskeletal trafficking (GO:0099518), negative regulation of proteasomal protein catabolic process (GO:1901799)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), early endosome (GO:0005769), nuclear body (GO:0016604), cytoplasm (GO:0005737), endosome (GO:0005768)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton-dependent intracellular transport	1
establishment of vesicle localization	1
proteasomal protein catabolic process	1
negative regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
binding	1
intracellular membrane-bounded organelle	1
endosome	1
nucleoplasm	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

308 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
F8A2	HTT	P42858	974
F8A2	RAB5A	P20339	953
F8A2	HAP1	P54257	583
F8A2	APPL1	Q9UKG1	481
F8A2	REPIN1	Q9BWE0	480
F8A2	NAPB	Q9H115	448
F8A2	ANKFY1	Q9P2R3	388
F8A2	RAB11A	P24410	365
F8A2	RAB8A	P24407	360
F8A2	KIF16B	Q96L93	349
F8A2	RBSN	Q9H1K0	348
F8A2	AP2S1	P53680	336
F8A2	NPIPB15	A6NHN6	327
F8A2	CLIC2	O15247	324
F8A2	SPRY3	O43610	323

IntAct

11 interactions, top by confidence:

A	B	Type	Score
F8A1	HTT	psi-mi:“MI:0915”(physical association)	0.780
RAB30	UBB	psi-mi:“MI:0914”(association)	0.530
F8A1	MTNR1A	psi-mi:“MI:0915”(physical association)	0.000
SH3GLB1	F8A1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): F8A1 (Affinity Capture-MS), F8A1 (Two-hybrid), F8A1 (Two-hybrid), F8A1 (Affinity Capture-Western), KPTN (Affinity Capture-MS), RASA2 (Affinity Capture-MS), ITFG2 (Affinity Capture-MS), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), CLUH (Affinity Capture-MS), ITFG2 (Affinity Capture-MS), F8A1 (Affinity Capture-MS), KPTN (Affinity Capture-MS), F8A1 (Proximity Label-MS), F8A1 (Positive Genetic)

ESM2 similar proteins: A5A779, A6NLP5, A8E7I5, C5IJB0, F1MX48, I3L5V6, M0RDU0, O35465, O95801, P23610, P36915, P36916, P97452, Q00558, Q08602, Q0P5H9, Q14137, Q14318, Q17QX2, Q2TBQ9, Q2YD98, Q3B7U9, Q3SZV0, Q4R588, Q4R8D2, Q5EA80, Q5NVK5, Q5R8E2, Q5RA07, Q5TM59, Q66H45, Q68G30, Q6AY79, Q6IMX7, Q6P597, Q6P9Z4, Q6SZW1, Q7YR35, Q810A3, Q8C3I8

Diamond homologs: M0RDU0, P23610, Q00558

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

61 predictions. Top by Δscore:

Variant	Effect	Δscore
X:155382295:G:GT	donor_gain	0.5900
X:155382904:G:GT	donor_gain	0.5500
X:155382294:G:GT	donor_gain	0.5300
X:155383002:G:GT	donor_gain	0.5200
X:155382296:A:T	donor_gain	0.4700
X:155382255:C:T	donor_gain	0.4400
X:155383005:G:GG	donor_gain	0.4200
X:155383004:A:AG	donor_gain	0.4100
X:155383040:A:T	donor_gain	0.4100
X:155382771:GC:G	donor_gain	0.3900
X:155383222:G:GT	donor_gain	0.3900
X:155382918:CTGCG:C	acceptor_gain	0.3700
X:155382231:G:GT	donor_gain	0.3600
X:155382921:CG:C	acceptor_gain	0.3600
X:155383082:A:AG	acceptor_gain	0.3600
X:155383083:G:GG	acceptor_gain	0.3600
X:155382271:C:G	donor_gain	0.3300
X:155382279:G:GT	donor_gain	0.3300
X:155383008:C:CG	donor_gain	0.3300
X:155382333:G:GA	donor_gain	0.3100
X:155382260:A:AG	donor_gain	0.3000
X:155382261:G:GG	donor_gain	0.3000
X:155382502:C:A	donor_gain	0.3000
X:155382915:C:A	donor_gain	0.3000
X:155383111:G:GT	donor_gain	0.3000
X:155382891:G:A	acceptor_gain	0.2900
X:155383014:G:GT	donor_gain	0.2900
X:155383063:G:GT	donor_gain	0.2900
X:155383117:G:GT	donor_gain	0.2900
X:155382320:GCC:G	donor_gain	0.2800

AlphaMissense

2313 scored. Top likely-pathogenic:

dbSNP variants (sampled 97 via entrez): RS1169387438 (X:155384188 G>A), RS1189279270 (X:155384130 TTTTTTTCC>T), RS1193045775 (X:155384133 TTTTCCCC>T), RS1204926434 (X:155383741 C>G), RS1209944426 (X:155381727 C>G), RS1219884560 (X:155384135 T>C), RS1240866348 (X:155384131 TTTTTTCC>T), RS1242135833 (X:155383925 T>C), RS1274843001 (X:155384135 TTCCCC>T), RS1282663906 (X:155382018 G>C), RS1285620659 (X:155383837 A>C), RS1292436304 (X:155384134 TTTCCCC>T), RS1297693216 (X:155384032 C>G), RS1321330082 (X:155384143 C>CCT), RS1332648413 (X:155384136 TCCCC>T,TC,TCC,TCCC,TCCCCC,TCCCCCC)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
chromium hexavalent ion	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Catechin	affects cotreatment, increases expression	1
Ozone	affects expression, increases abundance	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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