# NM_015230.4(ARAP2):c.1392C>T (p.Ala464=)

https://sugi.bio/variant/arap2-p-ala464

## Summary

**ARAP2 p.Ala464= (c.1392C>T)** is classified **Likely benign** in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). Rare (popmax 0.107%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs112385259 · 1 submitter · rare (popmax 0.107%, nfe)

## For patients & families {#patients}

This is a change in the ARAP2 gene that is classified as likely benign — not considered disease-causing, 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 | [ARAP2](https://sugi.bio/atlas/gene/ARAP2/) |
| Protein change (HGVS p.) | p.Ala464= |
| Coding change (HGVS c.) | c.1392C>T |
| MANE Select transcript | [NM_015230](https://www.ncbi.nlm.nih.gov/nuccore/NM_015230) |
| dbSNP | [rs112385259](https://www.ncbi.nlm.nih.gov/snp/rs112385259/) |
| Variant type | single nucleotide variant |
| Location | chr4:36210485-36210485 (GRCh38) |
| ClinVar | [VCV2654707](https://www.ncbi.nlm.nih.gov/clinvar/variation/2654707/) |

**All HGVS expressions:** `NC_000004.11:g.36212107G>A`, `NC_000004.12:g.36210485G>A`, `NM_015230.4:c.1392C>T`, `NR_146893.2:n.1882C>T`, `NR_146894.2:n.1887C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.92 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.116**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.41 acceptor loss), 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 **0.107%** (nfe) · FAF95 0.102% · FAF99 0.0999% · 1,261/1,179,838 in the highest group · 1,517/1,613,848 alleles overall — rare (popmax 0.107%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.112% | 893 |
| European (non-Finnish) (grpmax) | 0.107% | 936 |
| African / African-American | 0.105% | 949 |
| Finnish (not grpmax-eligible) | 0.0843% | 1,186 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0743% | 1,345 |
| Admixed American | 0.0467% | 2,143 |
| Middle Eastern | 0.0165% | 6,062 |
| East Asian | 0.00446% | 22,436 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ARAP2** population constraint: LOEUF 0.884, pLI 5.7363e-27, missense-Z -0.68052. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 67.42, 31% of residues very-high.

**2 experimental structure(s)** (PDB): [1X40](https://www.rcsb.org/structure/1X40), [2COD](https://www.rcsb.org/structure/2COD).

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

*Describes the biological roles of ARAP2 (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:** ARAP2's established molecular role includes phosphatidylinositol-3,4,5-trisphosphate binding.


### Pathways affected {#pathways}

ARAP2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |

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

**Molecular function:** phosphatidylinositol-3,4,5-trisphosphate binding.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ARAP2 variant pages (same residue, condition, or type): [ARAP2 p.Ala1241Thr](/variant/arap2-p-ala1241thr), [ARAP2 p.Ala1261Thr](/variant/arap2-p-ala1261thr), [ARAP2 p.Ala1261Val](/variant/arap2-p-ala1261val), [ARAP2 p.Ala1353Glu](/variant/arap2-p-ala1353glu), [ARAP2 p.Ala1375Pro](/variant/arap2-p-ala1375pro), [ARAP2 p.Ala1421Ser](/variant/arap2-p-ala1421ser), [ARAP2 p.Ala1421Thr](/variant/arap2-p-ala1421thr), [ARAP2 p.Ala1508Thr](/variant/arap2-p-ala1508thr).

### 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 2654707). 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.*