# NM_032389.6(ARFGAP2):c.1262C>T (p.Ala421Val)

https://sugi.bio/variant/arfgap2-p-ala421val

## Summary

**ARFGAP2 p.Ala421Val (c.1262C>T)** is classified **Uncertain significance** in ARFGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: ambiguous (0.5495); Very rare (popmax 0.004%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs139591977 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the ARFGAP2 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 | [ARFGAP2](https://sugi.bio/atlas/gene/ARFGAP2/) |
| Protein change (HGVS p.) | p.Ala421Val |
| Coding change (HGVS c.) | c.1262C>T |
| MANE Select transcript | [NM_032389](https://www.ncbi.nlm.nih.gov/nuccore/NM_032389) |
| dbSNP | [rs139591977](https://www.ncbi.nlm.nih.gov/snp/rs139591977/) |
| Variant type | single nucleotide variant |
| Location | chr11:47166830-47166830 (GRCh38) |
| ClinVar | [VCV2308052](https://www.ncbi.nlm.nih.gov/clinvar/variation/2308052/) |

**All HGVS expressions:** `NC_000011.10:g.47166830G>A`, `NC_000011.9:g.47188381G>A`, `NM_001242832.2:c.1178C>T`, `NM_001410995.1:c.1304C>T`, `NM_032389.6:c.1262C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5495) — no call either way
- REVEL 0.387 (indeterminate)
- SaProt LLR -10.073 (damaging)
- SpliceAI predicts **donor gain** (Δ 0.40) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.981, GERP 2.55, phastCons 1 — highly conserved
- 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 0.94** across the covering region of the MANE Select transcript (47,165,485–47,176,853), spanning 11,368 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.40**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.40**.
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00247% · FAF99 0.00217% · 3/74,926 in the highest group · 46/1,613,950 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.004% | 24,975 |
| European (non-Finnish) | 0.0033% | 30,257 |
| South Asian | 0.00329% | 30,361 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*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}

**ARFGAP2** population constraint: LOEUF 0.8, pLI 6.3036e-09, missense-Z 0.85046. *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 **421** lies in the 'required for interaction with coatomer' region.

AlphaFold model confidence (whole protein): pLDDT 66.19, 25% of residues very-high.

**1 experimental structure(s)** (PDB): [2P57](https://www.rcsb.org/structure/2P57).

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

*Describes the biological roles of ARFGAP2 (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}

ARFGAP2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [COPI-dependent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811434) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-07.

**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 | 2025-03-07 |

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

## Similar variants {#similar}

Related ARFGAP2 variant pages (same residue, condition, or type): [ARFGAP2 p.Ala227Thr](/variant/arfgap2-p-ala227thr), [ARFGAP2 p.Ala259Thr](/variant/arfgap2-p-ala259thr), [ARFGAP2 p.Ala266Val](/variant/arfgap2-p-ala266val), [ARFGAP2 p.Ala272Thr](/variant/arfgap2-p-ala272thr), [ARFGAP2 p.Ala443Val](/variant/arfgap2-p-ala443val), [ARFGAP2 p.Ala500Pro](/variant/arfgap2-p-ala500pro), [ARFGAP2 p.Arg119Trp](/variant/arfgap2-p-arg119trp), [ARFGAP2 p.Arg255Gly](/variant/arfgap2-p-arg255gly).

### 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 2308052). 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.*