# NM_001040118.3(ARAP1):c.716C>T (p.Pro239Leu)

https://sugi.bio/variant/arap1-p-pro239leu

## Summary

**ARAP1 p.Pro239Leu (c.716C>T)** is classified **Uncertain significance** in ARAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.066); Rare (popmax 0.165%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · rare (popmax 0.165%, amr)

## For patients & families {#patients}

This is a change in the ARAP1 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 | [ARAP1](https://sugi.bio/atlas/gene/ARAP1/) |
| Protein change (HGVS p.) | p.Pro239Leu |
| Coding change (HGVS c.) | c.716C>T |
| MANE Select transcript | [NM_001040118](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040118) |
| Variant type | single nucleotide variant |
| Location | chr11:72713207-72713207 (GRCh38) |
| ClinVar | [VCV4129558](https://www.ncbi.nlm.nih.gov/clinvar/variation/4129558/) |

**All HGVS expressions:** `NC_000011.10:g.72713207G>A`, `NC_000011.9:g.72424252G>A`, `NG_123462.1:g.666G>A`, `NM_001040118.3:c.716C>T`, `NM_001135190.2:c.-20C>T`, `NM_001369489.1:c.-20C>T`, `NM_015242.5:c.-20C>T`, `NR_161388.1:n.698C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.066)
- REVEL 0.014 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.468 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.151, GERP -3.81, phastCons 0.147 — weakly conserved position
- CADD: **PHRED 16.72**. 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 1.20** across the covering region of the MANE Select transcript (72,712,546–72,726,650), spanning 14,104 bp. Chi-square p 0.023. 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 (G>C, Δ0.29 donor 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 **0.165%** (amr) · FAF95 0.139% · FAF99 0.129% · 99/60,014 in the highest group · 156/1,613,990 alleles overall — rare (popmax 0.165%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.165% | 606 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,125 |
| Middle Eastern | 0.0165% | 6,058 |
| African / African-American | 0.00533% | 18,757 |
| East Asian | 0.00446% | 22,437 |
| European (non-Finnish) | 0.00237% | 42,140 |
| South Asian | 0.0022% | 45,535 |

*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}

**ARAP1** population constraint: LOEUF 0.572, pLI 1.1045e-06, missense-Z 1.8747. *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 **239** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 75.81, 41% of residues very-high.

**1 experimental structure(s)** (PDB): [4X1V](https://www.rcsb.org/structure/4X1V).

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

*Describes the biological roles of ARAP1 (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:** ARAP1's established molecular role includes GTPase activator activity. p.Pro239Leu falls in the disordered region.


### Pathways affected {#pathways}

ARAP1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1](https://reactome.org/content/detail/R-HSA-8849469) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |

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

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

**Biological process:** regulation of receptor internalization, regulation of cell shape, positive regulation of GTPase activity, positive regulation of filopodium assembly, negative regulation of stress fiber assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-05.

**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 | 2025-08-05 |

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

## Similar variants {#similar}

Related ARAP1 variant pages (same residue, condition, or type): [ARAP1 p.Gln1047Glu](/variant/arap1-p-gln1047glu), [ARAP1 p.Pro1039=](/variant/arap1-p-pro1039), [ARAP1 p.Pro254Leu](/variant/arap1-p-pro254leu), [ARAP1 p.Val1408Met](/variant/arap1-p-val1408met), [ARAP1 p.Ala1046Ser](/variant/arap1-p-ala1046ser), [ARAP1 p.Ala1124Thr](/variant/arap1-p-ala1124thr), [ARAP1 p.Ala1199Thr](/variant/arap1-p-ala1199thr), [ARAP1 p.Ala1389Thr](/variant/arap1-p-ala1389thr).

### 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 4129558). 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.*