# NM_001024807.3(APLP1):c.698C>G (p.Pro233Arg)

https://sugi.bio/variant/aplp1-p-pro233arg

## Summary

**APLP1 p.Pro233Arg (c.698C>G)** is classified **Uncertain significance** in APLP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-14). AlphaMissense: likely benign (0.0708); Very rare (popmax 0.00144%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs367773519 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00144%, nfe)

## For patients & families {#patients}

This is a change in the APLP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [APLP1](https://sugi.bio/atlas/gene/APLP1/) |
| Protein change (HGVS p.) | p.Pro233Arg |
| Coding change (HGVS c.) | c.698C>G |
| MANE Select transcript | [NM_001024807](https://www.ncbi.nlm.nih.gov/nuccore/NM_001024807) |
| dbSNP | [rs367773519](https://www.ncbi.nlm.nih.gov/snp/rs367773519/) |
| Variant type | single nucleotide variant |
| Location | chr19:35871884-35871884 (GRCh38) |
| ClinVar | [VCV2334671](https://www.ncbi.nlm.nih.gov/clinvar/variation/2334671/) |

**All HGVS expressions:** `LRG_693:g.2404G>C`, `NC_000019.10:g.35871884C>G`, `NC_000019.9:g.36362786C>G`, `NG_013356.2:g.2404G>C`, `NM_001024807.3:c.698C>G`, `NM_005166.5:c.698C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0708)
- REVEL 0.254 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.819 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -2.843, GERP -3.49 — fast-evolving / accelerated position
- CADD: **PHRED 0.696**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (35,868,680–35,872,030), spanning 3,350 bp. Chi-square p 0.81. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.46 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00144%** (nfe) · FAF95 0.000878% · FAF99 0.000717% · 17/1,180,000 in the highest group · 17/1,613,920 alleles overall — very rare (popmax 0.00144%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**APLP1** population constraint: LOEUF 0.713, pLI 1.1458e-07, missense-Z 0.63325. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **233** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 69.36, 34% of residues very-high.

**6 experimental structure(s)** (PDB): [3PMR](https://www.rcsb.org/structure/3PMR), [3Q7G](https://www.rcsb.org/structure/3Q7G), [3Q7L](https://www.rcsb.org/structure/3Q7L), [3QMK](https://www.rcsb.org/structure/3QMK), [4RD9](https://www.rcsb.org/structure/4RD9), [4RDA](https://www.rcsb.org/structure/4RDA).

## What this gene does {#gene-function}

*Describes the biological roles of APLP1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** APLP1's established molecular role includes alpha-2A adrenergic receptor binding. p.Pro233Arg falls in the disordered region.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** alpha-2A adrenergic receptor binding, alpha-2B adrenergic receptor binding, alpha-2C adrenergic receptor binding, identical protein binding.

**Biological process:** cellular response to norepinephrine stimulus, negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-14.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-12-14 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related APLP1 variant pages (same residue, condition, or type): [APLP1 p.Pro233Leu](/variant/aplp1-p-pro233leu), [APLP1 p.Ala149Asp](/variant/aplp1-p-ala149asp), [APLP1 p.Ala222Pro](/variant/aplp1-p-ala222pro), [APLP1 p.Ala263Thr](/variant/aplp1-p-ala263thr), [APLP1 p.Ala382Thr](/variant/aplp1-p-ala382thr), [APLP1 p.Ala391Val](/variant/aplp1-p-ala391val), [APLP1 p.Ala412Thr](/variant/aplp1-p-ala412thr), [APLP1 p.Ala47Glu](/variant/aplp1-p-ala47glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2334671). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*