APLP1

Summary

APLP1 (amyloid beta precursor like protein 1, HGNC:597) is a protein-coding gene on chromosome 19q13.12, encoding Amyloid beta precursor like protein 1 (P51693). May play a role in postsynaptic function.

This gene encodes a member of the highly conserved amyloid precursor protein gene family. The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor protein cleavage. This cleavage liberates an intracellular cytoplasmic fragment that may act as a transcriptional activator. The encoded protein may also play a role in synaptic maturation during cortical development. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 333 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 108 total
• GTEx eGene: eQTL in 20 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.71 (unconstrained)
• MANE Select transcript: NM_001024807
• Notable: 108 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:597
Approved symbol	APLP1
Name	amyloid beta precursor like protein 1
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	APLP
Ensembl gene	ENSG00000105290
Ensembl biotype	protein_coding
OMIM	104775
Entrez	333

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 36 protein_coding, 7 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000221891

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 4, TSL 3: 2, TSL 4: 1, TSL 5: 3

ENST00000221891, ENST00000537454, ENST00000586861, ENST00000587274, ENST00000588808, ENST00000589298, ENST00000589743, ENST00000590561, ENST00000590926, ENST00000591165, ENST00000592316, ENST00000652533, ENST00000898020, ENST00000898021, ENST00000898022, ENST00000898023, ENST00000898024, ENST00000898025, ENST00000898026, ENST00000898027, ENST00000898028, ENST00000898029, ENST00000898030, ENST00000898031, ENST00000898032, ENST00000898033, ENST00000898034, ENST00000898035, ENST00000898036, ENST00000898037, ENST00000912739, ENST00000912740, ENST00000960045, ENST00000960046, ENST00000960047, ENST00000960048, ENST00000960049, ENST00000997344, ENST00000997345, ENST00000997346, ENST00001032799, ENST00001032804, ENST00001032808, ENST00001032811, ENST00001032814, ENST00001142829

RefSeq mRNA: 2 — MANE Select: NM_001024807 NM_001024807, NM_005166

CCDS: CCDS32997, CCDS92600

Canonical transcript exons

ENST00000221891 — 17 exons

Exon	Start	End
ENSE00000699119	35869667	35869810
ENSE00000862892	35868574	35868783
ENSE00003481926	35874741	35874869
ENSE00003483225	35876517	35876616
ENSE00003514045	35878890	35878952
ENSE00003530982	35879074	35879217
ENSE00003555094	35879343	35879792
ENSE00003562024	35878082	35878108
ENSE00003565832	35874504	35874662
ENSE00003575855	35871612	35871745
ENSE00003608678	35871237	35871349
ENSE00003636208	35877718	35877825
ENSE00003655675	35871858	35872036
ENSE00003665284	35873639	35873713
ENSE00003680193	35878584	35878654
ENSE00003680703	35872483	35872613
ENSE00003760164	35870896	35871028

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 99.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.1604 / max 1292.6945, expressed in 1048 samples.

Highest expression (Bgee): C1 segment of cervical spinal cord, inferior olivary complex, spinal cord, middle frontal gyrus, frontal lobe.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APLP1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 20 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

20 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Aorta	eqtl	4.3e-28	+1.22	19:35879666:AATTT:A
Pancreas	eqtl	2.7e-13	+0.75	19:35870628:A:G
Nerve Tibial	eqtl	2.0e-12	+0.60	19:35880522:A:T
Cells Cultured fibroblasts	eqtl	4.5e-12	+0.59	19:35879666:AATTT:A
Lung	eqtl	4.1e-11	+0.75	19:35863704:G:A
Thyroid	eqtl	2.3e-06	+0.54	19:35884027:G:GTTTTT
Esophagus Muscularis	eqtl	2.8e-06	-0.43	19:35879953:G:A
Adipose Visceral Omentum	eqtl	9.2e-06	+0.58	19:35879666:AATTT:A
Esophagus Mucosa	eqtl	8.5e-05	+0.65	19:35884700:G:A
Skin Not Sun Exposed Suprapubic	eqtl	3.3e-04	+0.46	19:35884027:G:GTTTTT
Adipose Subcutaneous	eqtl	8.2e-04	+0.48	19:35851918:G:C
Muscle Skeletal	eqtl	1.3e-03	+0.59	19:35889544:G:A
Skin Sun Exposed Lower leg	eqtl	1.9e-03	+0.47	19:35858834:G:C
Breast Mammary Tissue	eqtl	3.4e-03	-0.97	19:36441906:C:T
Testis	eqtl	4.2e-03	+0.38	19:35892560:T:A
Artery Tibial	eqtl	1.1e-02	+0.31	19:35879666:AATTT:A
Heart Atrial Appendage	eqtl	1.7e-02	-0.72	19:35414501:G:A
Brain Anterior cingulate cortex BA24	eqtl	2.8e-02	-0.13	19:36310121:T:TA
Prostate	eqtl	3.1e-02	-0.89	19:35975135:G:A
Brain Hippocampus	eqtl	4.3e-02	-0.45	19:35465127:G:A

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
175413	13.6329	1008
175414	3.0908	367
175415	1.0983	107
175416	0.5580	97
175417	0.3179	110
175418	0.2350	84
175411	0.2274	110

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.86	gold quality
inferior olivary complex	UBERON:0002127	99.73	gold quality
spinal cord	UBERON:0002240	99.73	gold quality
middle frontal gyrus	UBERON:0002702	99.72	gold quality
right frontal lobe	UBERON:0002810	99.71	gold quality
prefrontal cortex	UBERON:0000451	99.65	gold quality
caudate nucleus	UBERON:0001873	99.58	gold quality
nucleus accumbens	UBERON:0001882	99.51	gold quality
cortical plate	UBERON:0005343	99.49	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.45	gold quality
amygdala	UBERON:0001876	99.42	gold quality
hypothalamus	UBERON:0001898	99.40	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.36	gold quality
anterior cingulate cortex	UBERON:0009835	99.30	gold quality
cingulate cortex	UBERON:0003027	99.29	gold quality
inferior vagus X ganglion	UBERON:0005363	99.29	gold quality
corpus callosum	UBERON:0002336	99.28	gold quality
frontal cortex	UBERON:0001870	99.24	gold quality
frontal lobe	UBERON:0016525	99.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.22	gold quality
putamen	UBERON:0001874	99.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.19	gold quality
cerebellar hemisphere	UBERON:0002245	99.09	gold quality
cerebellar cortex	UBERON:0002129	99.05	gold quality
Ammon’s horn	UBERON:0001954	99.03	gold quality
telencephalon	UBERON:0001893	99.00	gold quality
forebrain	UBERON:0001890	98.99	gold quality
neocortex	UBERON:0001950	98.99	gold quality
postcentral gyrus	UBERON:0002581	98.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.92	gold quality
temporal lobe	UBERON:0001871	98.89	gold quality
adenohypophysis	UBERON:0002196	98.87	gold quality
cerebral cortex	UBERON:0000956	98.84	gold quality
parietal lobe	UBERON:0001872	98.82	gold quality
central nervous system	UBERON:0001017	98.81	gold quality
ganglionic eminence	UBERON:0004023	98.79	gold quality
brain	UBERON:0000955	98.78	gold quality
medulla oblongata	UBERON:0001896	98.77	gold quality
pituitary gland	UBERON:0000007	98.76	gold quality
subthalamic nucleus	UBERON:0001906	98.71	gold quality
frontal pole	UBERON:0002795	98.53	gold quality
cerebellum	UBERON:0002037	98.52	gold quality
entorhinal cortex	UBERON:0002728	98.41	gold quality
ventral tegmental area	UBERON:0002691	98.32	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.23	gold quality
lateral globus pallidus	UBERON:0002476	98.22	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.19	gold quality
superior vestibular nucleus	UBERON:0007227	98.16	gold quality
pons	UBERON:0000988	98.08	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.02	gold quality
cranial nerve II	UBERON:0000941	97.89	gold quality
superior frontal gyrus	UBERON:0002661	97.87	gold quality
midbrain	UBERON:0001891	97.61	gold quality
globus pallidus	UBERON:0001875	97.58	gold quality
paraflocculus	UBERON:0005351	97.56	gold quality
substantia nigra	UBERON:0002038	97.52	gold quality
medial globus pallidus	UBERON:0002477	97.36	gold quality
islet of Langerhans	UBERON:0000006	97.30	gold quality
substantia nigra pars compacta	UBERON:0001965	97.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.02	gold quality
CA1 field of hippocampus	UBERON:0003881	96.91	gold quality
ventricular zone	UBERON:0003053	96.39	gold quality
orbitofrontal cortex	UBERON:0004167	96.19	gold quality
body of pancreas	UBERON:0001150	95.87	gold quality
pancreas	UBERON:0001264	94.55	gold quality
occipital lobe	UBERON:0002021	94.43	gold quality
pigmented layer of retina	UBERON:0001782	94.07	gold quality
retina	UBERON:0000966	94.05	gold quality
middle temporal gyrus	UBERON:0002771	94.03	gold quality
primary visual cortex	UBERON:0002436	93.21	gold quality
cerebellar vermis	UBERON:0004720	92.76	gold quality
adult organism	UBERON:0007023	90.58	gold quality
embryo	UBERON:0000922	89.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.84	gold quality
body of stomach	UBERON:0001161	88.83	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.94	gold quality
right testis	UBERON:0004534	87.41	gold quality
apex of heart	UBERON:0002098	87.21	gold quality
stomach	UBERON:0000945	86.95	gold quality
left testis	UBERON:0004533	86.58	gold quality
olfactory bulb	UBERON:0002264	85.92	gold quality
ascending aorta	UBERON:0001496	85.74	gold quality
thoracic aorta	UBERON:0001515	85.55	gold quality
right atrium auricular region	UBERON:0006631	84.53	gold quality
testis	UBERON:0000473	84.43	gold quality
descending thoracic aorta	UBERON:0002345	84.43	gold quality
heart left ventricle	UBERON:0002084	83.51	gold quality
fundus of stomach	UBERON:0001160	83.34	gold quality
cardiac atrium	UBERON:0002081	83.11	gold quality
cardiac ventricle	UBERON:0002082	83.07	gold quality
endometrium epithelium	UBERON:0004811	82.80	gold quality
stromal cell of endometrium	CL:0002255	82.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.90	gold quality
aorta	UBERON:0000947	81.60	gold quality
type B pancreatic cell	CL:0000169	81.57	silver quality
heart	UBERON:0000948	81.43	gold quality
dorsal root ganglion	UBERON:0000044	80.91	gold quality
cardia of stomach	UBERON:0001162	80.23	gold quality
right coronary artery	UBERON:0001625	80.23	gold quality
peripheral nervous system	UBERON:0000010	79.31	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	1571.82
E-HCAD-25	yes	51.08
E-GEOD-81547	yes	25.87
E-HCAD-5	yes	20.71
E-GEOD-84465	yes	14.35
E-GEOD-135922	yes	13.01
E-GEOD-93593	yes	12.17
E-GEOD-83139	yes	4.16
E-HCAD-10	yes	4.08
E-MTAB-10485	no	561.20
E-ENAD-27	no	3.27
E-HCAD-31	no	3.26
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	1487.4
Caudate putamen	tissue	1157.9
Spinal cord	tissue	1038.1
Frontal cortex	tissue	966.8
Medulla oblongata	tissue	935.4
Midbrain	tissue	909.6
Thalamus	tissue	728.7
Substantia nigra	tissue	727.9
Putamen	tissue	700.2
Nucleus accumbens	tissue	689.5
Superior colliculi	tissue	683.0
Pons	tissue	668.9
Ventral forebrain	tissue	607.3
Hippocampal formation	tissue	591.7
Periaqueductal gray	tissue	504.2
Cerebral cortex	tissue	478.4	medium
Somatosensory cortex	tissue	478.4
Hypothalamus	tissue	474.0
Septum	tissue	467.8
Hippocampus	tissue	467.5	medium
Basal ganglia	tissue	466.5	medium
Locus coeruleus	tissue	465.6
Prefrontal cortex	tissue	437.2
Motor cortex	tissue	435.6
Occipital cortex	tissue	432.1
Retrosplenial cortex	tissue	411.8
Retrosplenial and cingulate cortex	tissue	391.3
Temporal cortex	tissue	385.6
Postcentral gyrus	tissue	382.5
Entorhinal cortex	tissue	367.0
Insular cortex	tissue	354.1
Amygdala	tissue	342.3
Olfactory bulb	tissue	218.9
Cerebellum	tissue	185.3	high
Pituitary gland	tissue	133.6
Choroid plexus	tissue	122.8
Pancreas	tissue	70.8	not detected
Retina	tissue	52.1
Adrenal gland	tissue	29.5	not detected
Parathyroid gland	tissue	20.9	not detected
Stomach 1	tissue	16.6	not detected
Heart muscle	tissue	9.3	not detected
Testis	tissue	8.4	not detected
Gallbladder	tissue	5.1	not detected
Smooth muscle	tissue	3.0	not detected
Appendix	tissue	2.9	not detected
Adipose tissue	tissue	2.2	not detected
Colon	tissue	2.2	not detected
Rectum	tissue	2.1	not detected
Small intestine	tissue	1.9	not detected
Vagina	tissue	1.8	not detected
Seminal vesicle	tissue	1.8	not detected
Lung	tissue	1.8	not detected
Salivary gland	tissue	1.7	not detected
Endometrium 1	tissue	1.7	not detected
Duodenum	tissue	1.7	not detected
Kidney	tissue	1.6	not detected
Prostate	tissue	1.6	not detected
Esophagus	tissue	1.4	not detected
Tonsil	tissue	1.4	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Parieto-temporal junction (white matter) (2100.6), Corpus callosum, splenium (white matter) (1707.1), Temporal white matter (1633.6), Corpus callosum, genu (white matter) (1576.8), Cerebellar white matter (1522.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

Targeting APLP1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

27 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-340-3P	98.11	68.25	679
HSA-MIR-6757-5P	98.08	65.50	724
HSA-MIR-6827-3P	98.08	72.27	651
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-450B-3P	97.56	66.12	512
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-769-3P	97.06	64.83	464
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-8083	95.93	67.55	694
HSA-MIR-1298-3P	94.05	64.84	620

Functional genomics

gnomAD constraint: pLI 1.15e-07, LOEUF 0.713, missense Z 0.633 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000221891 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
19:35,868,637–35,868,679	10 / 25.4	0.39	no
19:35,868,680–35,872,030	383 / 378.3	1.01	no
19:35,872,031–35,879,438	433 / 496.5	0.87	no

Literature-anchored findings (GeneRIF, showing 23)

• APLP1 and APLP2 are processed by the gamma-secretase in a Presenilin 1-dependent manner and the extreme carboxyl-terminal fragments produced by this processing (APP-like Intracellular Domain) are able to enhance Fe65-dependent gene activation (PMID:12228233)
• APLP1 does not undergo the same type of regulated processing as APP and APLP2. (PMID:14597230)
• APLP1 and APLP2 and APP are processed similarly to act via the same nuclear target and are regulated by BACE 1 in neurons (PMID:14699153)
• APLP-1 and APLP-2 are processed by alpha- and gamma-secretase-like cleavages, and their intracellular domains can be released by cleavage at epsilon-sites. APLP-2 processing appears to be the most elaborate and to involve alternative cleavage sites. (PMID:14970212)
• The 5’ UTR of the Aplp1 gene lacks any type of CAGA box. This may explain its inability to form amyloid plaques. (PMID:15208260)
• APLP1 affects the endocytosis of APP and makes more APP available for alpha-secretase cleavage (PMID:16344553)
• These results suggest a possible role of APLP1 in regulation of alpha2A-adrenergic receptor trafficking. (PMID:16531006)
• APLP1 is differentially upregulated in gastrointestinal neuroendocrine tumours and may be important for the dissemination of small intestinal carcinoids (PMID:18430897)
• Coexpression of APP with APLP1 or APLP2 leads to diminished generation of Abeta42 (PMID:19126676)
• neither cell-derived nor chemically synthesized APLP1-derived peptide influences the oligomerization or aggregation of Abeta (PMID:19401174)
• Human cerebrospinal fluid contains three APLP1-derived Abeta-like peptides that are generated by beta- and gamma-cleavages at a concentration of approximately 4.5 nM. (PMID:20049724)
• Both APLP1 and APLP2, form transcriptionally active triple protein complexes with Mint3 and transcriptional co-activators Taz andYap. (PMID:21178287)
• The 2.1 A resolution electron density map reveals phosphate ions that are bound to the protein surface. Mutational analysis shows that protein residues interacting with the phosphate ions are also involved in heparin binding. (PMID:21574595)
• [review] APP and its mammalian homologs, amyloid precursor-like proteins APLP1 and APLP2, participate under physiological conditions via trans-cellular dimerization in synaptogenesis. (PMID:21952790)
• APLP1 binds the II-III loop of the Ca(v)2.3 calcium channel and that this binding promotes internalization of the channel. (PMID:22178872)
• APLP1 has a regulatory role in the nuclear translocation of APP family intracellular domains due to the sequestration of Fe65. (PMID:23874953)
• CSF levels of 3 endogenous peptides derived from APLP1 (APL1beta25, APL1beta27 and APL1beta28) were decreased in Down syndrome. (PMID:24740518)
• APLP1 and APLP2, behave similarly to APP in that they both associate with assembled NMDA receptors in the endoplasmic reticulum (PMID:25683482)
• These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins. (PMID:25760599)
• The results show that in cognitively normal young adults carrying APlp1 mutations showed different spontaneous brain activity patterns without cerebral structural differences. (PMID:28987665)
• Results provide direct evidence that APLP1 functions as a neuronal zinc-dependent adhesion protein and allow a more detailed understanding of the molecular mechanisms driving the formation of APLP1 adhesion platforms. (PMID:29021345)
• The direct cleavage of APLP1 is a novel feature of the gamma-secretase. (PMID:29382944)
• Aplp1 interacts with Lag3 to facilitate transmission of pathologic alpha-synuclein. (PMID:38821932)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aplp1	ENSDARG00000098368
mus_musculus	Aplp1	ENSMUSG00000006651
rattus_norvegicus	Aplp1	ENSRNOG00000020851
drosophila_melanogaster	Appl	FBGN0000108
caenorhabditis_elegans		WBGENE00000149

Paralogs (2): APLP2 (ENSG00000084234), APP (ENSG00000142192)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88046) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	P53601	100.0%	Diamond
Sus scrofa	P79307	100.0%	Diamond
Pan troglodytes	Q5IS80	100.0%	Diamond
Cavia porcellus	Q60495	100.0%	Diamond
Saimiri sciureus	Q95241	100.0%	Diamond
Dichotomyctere fluviatilis	O73683	83.9%	Diamond
Takifugu rubripes	O93279	80.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
HCST	protein-coding	10870
NPHS1	protein-coding	4868
KIRREL2	protein-coding	84063
NFKBID	protein-coding	84807
PRODH2	protein-coding	58510
ARHGAP33	protein-coding	115703
TYROBP	protein-coding	7305

Protein

Protein identifiers

Amyloid beta precursor like protein 1 — P51693 (reviewed: P51693)

Alternative names: Amyloid beta (A4) precursor-like protein 1, Amyloid-like protein 1

All UniProt accessions (8): B7Z4G8, P51693, F5GZ08, K7ELK0, K7EMN4, K7EMS1, K7EQJ4, S4R3U6

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in postsynaptic function. The C-terminal gamma-secretase processed fragment, ALID1, activates transcription activation through APBB1 (Fe65) binding. Couples to JIP signal transduction through C-terminal binding. May interact with cellular G protein signaling pathways. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I. The gamma-CTF peptide, C30, is a potent enhancer of neuronal apoptosis.

Subunit / interactions. Monomer and homodimer. Heparin binding promotes homodimerization. Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB and APBA family members, MAPK8IP1 and DAB1. Binding to Dab1 inhibits its serine phosphorylation. Interacts with CPEB1. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Interacts (via NPXY motif) with DAB1.

Subcellular location. Cell membrane Cytoplasm.

Tissue specificity. Expressed in the cerebral cortex where it is localized to the postsynaptic density (PSD).

Post-translational modifications. Proteolytically cleaved by caspases during neuronal apoptosis. Cleaved, in vitro, at Asp-620 by caspase-3. N- and O-glycosylated. O-glycosylation with core 1 or possibly core 8 glycans. Glycosylation on Ser-227 is the preferred site to Thr-228.

Domain organisation. The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The NPXY site is also involved in clathrin-mediated endocytosis.

Miscellaneous. Binds zinc and copper in the extracellular domain. Zinc-binding increases heparin binding. No Cu(2+) reducing activity with copper-binding.

Similarity. Belongs to the APP family.

Isoforms (2)

UniProt ID	Names	Canonical?
P51693-1	1	yes
P51693-2	2

RefSeq proteins (2): NP_001019978, NP_005157 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008154	Amyloid_glyco_extra	Domain
IPR008155	Amyloid_glyco	Family
IPR011178	Amyloid_glyco_Cu-bd	Domain
IPR015849	Amyloid_glyco_heparin-bd	Domain
IPR019543	APP_amyloid_C	Domain
IPR019744	APP_CUBD_CS	Conserved_site
IPR019745	Amyloid_glyco_intracell_CS	Conserved_site
IPR024329	Amyloid_glyco_E2_domain	Domain
IPR036176	E2_sf	Homologous_superfamily
IPR036454	Amyloid_glyco_heparin-bd_sf	Homologous_superfamily
IPR036669	Amyloid_Cu-bd_sf	Homologous_superfamily

Pfam: PF02177, PF10515, PF12924, PF12925

UniProt features (59 total): region of interest 10, helix 7, binding site 6, glycosylation site 6, disulfide bond 6, short sequence motif 3, mutagenesis site 3, compositionally biased region 2, topological domain 2, sequence conflict 2, strand 2, turn 2, domain 2, signal peptide 1, chain 1, peptide 1, site 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
3PMR	Crystal Structure of E2 domain of Human Amyloid Precursor-Like Protein 1	X-RAY DIFFRACTION	2.11
3Q7L	Crystal structure of the E2 domain of amyloid precursor-like protein 1	X-RAY DIFFRACTION	2.2
3QMK	Crystal structure of the E2 domain of APLP1 in complex with heparin hexasaccharide	X-RAY DIFFRACTION	2.21
3Q7G	Crystal Structure of E2 domain of Human Amyloid Precursor-Like Protein 1 in complex with …	X-RAY DIFFRACTION	2.3
4RDA	X-RAY STRUCTURE OF THE AMYLOID PRECURSOR PROTEIN-LIKE PROTEIN 1 (APLP1) E2 DOMAIN IN …	X-RAY DIFFRACTION	2.5
4RD9	X-RAY STRUCTURE OF THE APO FORM OF THE AMYLOID PRECURSOR PROTEIN-LIKE PROTEIN 1 (APLP1) …	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51693-F1	69.36	0.34

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; plasma membrane; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Catalytic / active sites (1)

Position	Role
620–621	cleavage; by caspase-3

Ligand- & substrate-binding residues (6)

Position	Role
174	Cu(2+)
206	Zn(2+)
209	Zn(2+)
210	Zn(2+)
561	Cu(2+)
561	Zn(2+)

Disulfide bonds (6)

Type	Positions
Disulfide bond	60–84, 95–140, 120–128, 156–210, 167–197, 181–209

Glycosylation sites (6)

Type	Positions
O-linked (galnac…) threonine	215, 228
O-linked (galnac…) serine	227
N-linked (glcnac…) asparagine	337, 461, 551

Mutagenesis-validated functional residues (3)

Position	Phenotype
426	reduced affinity for heparin. reduces homodimerization.
429	strongly reduced affinity for heparin. strongly reduced homodimerization.
433	reduced affinity for heparin. reduces homodimerization.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 218 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GRUETZMANN_PANCREATIC_CANCER_DN, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, AP2_Q3, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_FOREBRAIN_DEVELOPMENT, TANG_SENESCENCE_TP53_TARGETS_UP, GOBP_TRANSLATION, MODULE_66, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (12): endocytosis (GO:0006897), apoptotic process (GO:0006915), cell adhesion (GO:0007155), nervous system development (GO:0007399), axonogenesis (GO:0007409), central nervous system development (GO:0007417), animal organ morphogenesis (GO:0009887), extracellular matrix organization (GO:0030198), forebrain development (GO:0030900), cellular response to norepinephrine stimulus (GO:0071874), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), animal organ development (GO:0048513)

GO Molecular Function (8): heparin binding (GO:0008201), alpha-2A adrenergic receptor binding (GO:0031694), alpha-2B adrenergic receptor binding (GO:0031695), alpha-2C adrenergic receptor binding (GO:0031696), identical protein binding (GO:0042802), transition metal ion binding (GO:0046914), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): basement membrane (GO:0005604), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

40 GO namespaces:

Category	Terms
animal gross anatomical part developmental process	4
cellular anatomical structure	4
adrenergic receptor binding	3
system development	2
cytoplasm	2
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular process	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
anatomical structure morphogenesis	1
animal organ development	1
extracellular structure organization	1
external encapsulating structure organization	1
brain development	1
cellular response to catecholamine stimulus	1
response to norepinephrine	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
negative regulation of G protein-coupled receptor signaling pathway	1
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
glycosaminoglycan binding	1
sulfur compound binding	1
protein binding	1
metal ion binding	1
binding	1
cation binding	1
extracellular matrix	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
intracellular anatomical structure	1
vacuole	1
plasma membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to norepinephrine stimulus	BP	direct assay
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	BP	direct assay
perinuclear region of cytoplasm	CC	direct assay
plasma membrane	CC	direct assay
alpha-2A adrenergic receptor binding	MF	physical interaction
alpha-2B adrenergic receptor binding	MF	physical interaction
alpha-2C adrenergic receptor binding	MF	physical interaction
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,595 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APLP1	CNOT11	Q9UKZ1	800
APLP1	APBB1	O00213	795
APLP1	BACE1	P56817	773
APLP1	APBB2	Q92870	661
APLP1	PSEN1	P49768	644
APLP1	ADAM10	O14672	642
APLP1	PSENEN	Q9NZ42	635
APLP1	NCSTN	Q92542	616
APLP1	APH1A	Q96BI3	595
APLP1	PSEN2	P49810	590
APLP1	MME	P08473	569
APLP1	APBA1	Q02410	560
APLP1	HMOX2	P30519	552
APLP1	C12orf57	Q99622	547
APLP1	MMEL1	Q495T6	537

IntAct

Human interaction partners of APLP1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 43 partners by confidence:

Partner	Interaction type	MIscore	Records
VPS29	physical association	0.560	3
TK1	physical association	0.550	2
TSC22D1	physical association	0.550	2
GLP1R	physical association	0.540	4
APLP2	physical association	0.540	2
APP	physical association	0.540	2
ZNF24	physical association	0.510	2
MED12	direct interaction	0.440	2
CNTN3	direct interaction	0.440	1
CNTN4	direct interaction	0.440	1
CNTN5	direct interaction	0.440	1
PILRA	physical association	0.400	1
SPON1	physical association	0.400	1
ANXA7	physical association	0.370	1
CDK4	physical association	0.370	1
CDKN1A	physical association	0.370	1
CSNK2B	physical association	0.370	1
ERBB2	physical association	0.370	1
PIN1	physical association	0.370	1
RAP1B	physical association	0.370	1
RCC1	physical association	0.370	1
SMN1	physical association	0.370	1
SNCA	physical association	0.370	1
VIM	physical association	0.370	1
MED4	association	0.350	1
CDKN2C	physical association	0.000	1
CRCT1	physical association	0.000	1
EIF2S2	physical association	0.000	1
FOS	physical association	0.000	1
GSTM4	physical association	0.000	1

BioGRID (67 interactions; top human partners by supporting records): APBB1 (Affinity Capture-MS; 3 records), APBB2 (Affinity Capture-MS; 3 records), APBB3 (Affinity Capture-MS; 3 records), DAB1 (Reconstituted Complex; 3 records), ERBB2 (Two-hybrid; 2 records), GLP1R (PCA; 2 records), TK1 (Two-hybrid; 2 records), TSC22D1 (Two-hybrid; 2 records), UTP14A (Two-hybrid; 2 records), ZNF24 (Two-hybrid; 2 records), ANXA7 (Two-hybrid), ARRB1 (Affinity Capture-MS), BSG (Proximity Label-MS), CDK4 (Two-hybrid), CDKN1A (Two-hybrid)

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
APLP1-MED12-MED23-MED4 complex (incomplete Mediator complex)	4	APLP1, MED12, MED23, MED4
★ ADRA2A-APLP1 complex	2	ADRA2A, APLP1
★ ADRA2B-APLP1 complex	2	APLP1, ADRA2B
★ ADRA2C-APLP1 complex	2	ADRA2C, APLP1

Disease & clinical

Genetic variants

Variant evidence for APLP1: 108 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	82
Likely benign	5
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 1,213):

Position(s)	Effect	Δscore	Sites
19:35868784–35868785	donor_loss	1.0000	5
19:35872037–35872038	donor_loss	1.0000	5
19:35873637–35873638	acceptor_loss	1.0000	5
19:35873714–35873715	donor_loss	1.0000	3
19:35874478	acceptor_gain	1.0000
19:35874484	acceptor_gain	1.0000
19:35874492–35874494	acceptor_gain	1.0000	2
19:35874502–35874503	acceptor_loss	1.0000	6
19:35874649	donor_gain	1.0000
19:35874663–35874664	donor_loss	1.0000	4

AlphaMissense

1,066 missense substitutions predicted likely pathogenic (of 4,211 scored), across 288 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M329	9	0.961	0.998
H376	8	0.989	0.997
F158	8	0.978	1.000
F354	8	0.977	1.000
N640	8	0.967	0.993
H307	8	0.943	0.968
H426	8	0.940	0.990
D336	8	0.927	0.979
H160	8	0.917	0.992
H433	8	0.899	0.988
S147	8	0.880	0.990
H353	8	0.839	0.995
H452	8	0.805	0.964
D295	8	0.803	0.909
D77	8	0.729	0.863
W332	7	0.998	1.000
F310	7	0.996	0.999
C156	7	0.992	0.998
C181	7	0.990	0.997
C140	7	0.988	0.996

HPA cancer prognostics

RNA cancer specificity: Group enriched (Glioblastoma Multiforme, Pancreatic Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	3.17e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	6.21e-05
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	6.83e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000694

Disease associations

OMIM: gene MIM:104775 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST003123_32	Severe influenza A (H1N1) infection	2e-13

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	3
Doxorubicin	increases expression	3
Valproic Acid	increases expression, affects expression	3
Aflatoxin B1	affects expression, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
nickel acetate	decreases reaction, increases expression, decreases expression	1
pyrimidifen	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
pyrachlostrobin	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimycin A	decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, affects localization	1
Dactinomycin	increases expression, affects cotreatment	1
Edetic Acid	decreases reaction, affects localization	1
Estradiol	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Rotenone	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.