# NM_022481.6(ARAP3):c.2953C>T (p.Arg985Cys)

https://sugi.bio/variant/arap3-p-arg985cys

## Summary

**ARAP3 p.Arg985Cys (c.2953C>T)** is classified **Uncertain significance** in ARAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely pathogenic (0.969); Very rare (popmax 0.0022%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs866209168 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the ARAP3 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 | [ARAP3](https://sugi.bio/atlas/gene/ARAP3/) |
| Protein change (HGVS p.) | p.Arg985Cys |
| Coding change (HGVS c.) | c.2953C>T |
| MANE Select transcript | [NM_022481](https://www.ncbi.nlm.nih.gov/nuccore/NM_022481) |
| dbSNP | [rs866209168](https://www.ncbi.nlm.nih.gov/snp/rs866209168/) |
| Variant type | single nucleotide variant |
| Location | chr5:141662103-141662103 (GRCh38) |
| ClinVar | [VCV2232294](https://www.ncbi.nlm.nih.gov/clinvar/variation/2232294/) |

**All HGVS expressions:** `NC_000005.10:g.141662103G>A`, `NC_000005.9:g.141041670G>A`, `NG_046966.1:g.25131C>T`, `NM_022481.6:c.2953C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.969)
- REVEL 0.498 (indeterminate)
- SaProt LLR -11.22 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 8.676, GERP 2.58, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in ARAP3 (of 8,990 modeled).
- CADD: **PHRED 33.0**. 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 0.86** across the covering region of the MANE Select transcript (141,653,953–141,671,744), spanning 17,791 bp. Chi-square p 1.3e-06. 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, Δ0.78 donor 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 **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/91,084 in the highest group · 2/1,461,894 alleles overall — very rare (popmax 0.0022%, sas).

*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}

**ARAP3** population constraint: LOEUF 0.598, pLI 1.0218e-09, missense-Z 2.5014. *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 **985** lies in the rho-gap domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 68.20, 23% of residues very-high.

**7 experimental structure(s)** (PDB): [2KG5](https://www.rcsb.org/structure/2KG5), [2LNW](https://www.rcsb.org/structure/2LNW), [5JCP](https://www.rcsb.org/structure/5JCP), [5JD0](https://www.rcsb.org/structure/5JD0), [7A9B](https://www.rcsb.org/structure/7A9B), [7YIR](https://www.rcsb.org/structure/7YIR).

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

*Describes the biological roles of ARAP3 (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:** ARAP3's established molecular role includes phosphatidylinositol-3,4,5-trisphosphate binding. p.Arg985Cys falls in the rho-gap domain.


### Pathways affected {#pathways}

ARAP3 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, phosphatidylinositol-3,4-bisphosphate binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-11.

**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 | 2021-06-11 |

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

## Similar variants {#similar}

Related ARAP3 variant pages (same residue, condition, or type): [ARAP3 p.Ala1045Val](/variant/arap3-p-ala1045val), [ARAP3 p.Ala10Thr](/variant/arap3-p-ala10thr), [ARAP3 p.Ala1159Val](/variant/arap3-p-ala1159val), [ARAP3 p.Ala1276Ser](/variant/arap3-p-ala1276ser), [ARAP3 p.Ala1342Thr](/variant/arap3-p-ala1342thr), [ARAP3 p.Ala216Asp](/variant/arap3-p-ala216asp), [ARAP3 p.Ala22Val](/variant/arap3-p-ala22val), [ARAP3 p.Ala36Thr](/variant/arap3-p-ala36thr).

### 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 2232294). 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.*