# NM_001282290.2(ARHGAP27):c.1747C>T (p.Arg583Trp)

https://sugi.bio/variant/arhgap27-p-arg583trp

## Summary

**ARHGAP27 p.Arg583Trp (c.1747C>T)** is classified **Uncertain significance** in ARHGAP27 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely benign (0.1632); Very rare (popmax 0.00535%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs368752990 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00535%, afr)

## For patients & families {#patients}

This is a change in the ARHGAP27 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 | [ARHGAP27](https://sugi.bio/atlas/gene/ARHGAP27/) |
| Protein change (HGVS p.) | p.Arg583Trp |
| Coding change (HGVS c.) | c.1747C>T |
| MANE Select transcript | [NM_001282290](https://www.ncbi.nlm.nih.gov/nuccore/NM_001282290) |
| dbSNP | [rs368752990](https://www.ncbi.nlm.nih.gov/snp/rs368752990/) |
| Variant type | single nucleotide variant |
| Location | chr17:45398044-45398044 (GRCh38) |
| ClinVar | [VCV3128696](https://www.ncbi.nlm.nih.gov/clinvar/variation/3128696/) |

**All HGVS expressions:** `NC_000017.10:g.43475410G>A`, `NC_000017.11:g.45398044G>A`, `NM_001282290.2:c.1747C>T`, `NM_001385384.1:c.1681C>T`, `NM_001385385.1:c.1147C>T`, `NM_001385386.1:c.1081C>T`, `NM_001385387.1:c.1081C>T`, `NM_001385388.1:c.1081C>T`, `NM_001385389.1:c.1147C>T`, `NM_001385390.1:c.976C>T`, `NM_001385391.1:c.910C>T`, `NM_001385392.1:c.910C>T`, `NM_001385393.1:c.724C>T`, `NM_001385394.1:c.658C>T`, `NM_001385395.1:c.724C>T`, `NM_001385396.1:c.658C>T`, `NM_001385397.1:c.532C>T`, `NM_001385398.1:c.466C>T`, `NM_001385399.1:c.466C>T`, `NM_199282.3:c.724C>T`, `NR_169600.1:n.1882C>T`, `NR_169601.1:n.2150C>T`, `NR_169602.1:n.990C>T`, `NR_169603.1:n.1179C>T`, `NR_169604.1:n.1160C>T`, `NR_169605.1:n.989C>T`, `NR_169606.1:n.1056C>T`, `NR_169607.1:n.1160C>T`, `NR_169608.1:n.1094C>T`, `NR_169609.1:n.1094C>T`, `NR_169610.1:n.1245C>T`, `NR_169611.1:n.1179C>T`, `NR_169612.1:n.1179C>T`, `NR_169613.1:n.1179C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1632)
- REVEL 0.631 (indeterminate)
- SaProt LLR -13.895 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 8.328, GERP 1.75, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.70 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 **0.00535%** (afr) · FAF95 0.0031% · FAF99 0.00277% · 4/74,792 in the highest group · 59/1,600,932 alleles overall — very rare (popmax 0.00535%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00811% | 12,331 |
| African / African-American (grpmax) | 0.00535% | 18,698 |
| European (non-Finnish) | 0.00402% | 24,900 |
| East Asian | 0.00224% | 44,662 |
| Admixed American | 0.00168% | 59,682 |
| South Asian | 0.00111% | 90,116 |

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}

**ARHGAP27** population constraint: LOEUF 0.709, pLI 3.8325e-08, missense-Z -0.12875. *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 **583** lies in a β-strand; the ph domain.

AlphaFold model confidence (whole protein): pLDDT 67.53, 30% of residues very-high.

**1 experimental structure(s)** (PDB): [3PP2](https://www.rcsb.org/structure/3PP2).

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

*Describes the biological roles of ARHGAP27 (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.*


### Pathways affected {#pathways}

ARHGAP27 participates in **2 Reactome pathways** (⚕ = disease pathway):

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-25.

**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 | 2023-10-25 |

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

## Similar variants {#similar}

Related ARHGAP27 variant pages (same residue, condition, or type): [ARHGAP27 c.657+107G>T](/variant/arhgap27-c-657-plus-107g-t), [ARHGAP27 c.657+130G>A](/variant/arhgap27-c-657-plus-130g-a), [ARHGAP27 c.657+26G>A](/variant/arhgap27-c-657-plus-26g-a), [ARHGAP27 c.657+31G>A](/variant/arhgap27-c-657-plus-31g-a), [ARHGAP27 c.657+34T>A](/variant/arhgap27-c-657-plus-34t-a), [ARHGAP27 c.657+38G>A](/variant/arhgap27-c-657-plus-38g-a), [ARHGAP27 c.657+49C>T](/variant/arhgap27-c-657-plus-49c-t), [ARHGAP27 c.657+53C>T](/variant/arhgap27-c-657-plus-53c-t).

### 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 3128696). 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.*