# NM_001658.4(ARF1):c.392C>G (p.Pro131Arg)

https://sugi.bio/variant/arf1-p-pro131arg

## Summary

**ARF1 p.Pro131Arg (c.392C>G)** is classified **Pathogenic** in ARF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). AlphaMissense: likely pathogenic (0.9416); Absent from gnomAD v4.1; Associated with periventricular nodular heterotopia 8.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2124858360 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ARF1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to periventricular nodular heterotopia 8.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016303/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ARF1](https://sugi.bio/atlas/gene/ARF1/) |
| Protein change (HGVS p.) | p.Pro131Arg |
| Coding change (HGVS c.) | c.392C>G |
| MANE Select transcript | [NM_001658](https://www.ncbi.nlm.nih.gov/nuccore/NM_001658) |
| dbSNP | [rs2124858360](https://www.ncbi.nlm.nih.gov/snp/rs2124858360/) |
| Variant type | single nucleotide variant |
| Location | chr1:228097859-228097859 (GRCh38) |
| ClinVar | [VCV1343799](https://www.ncbi.nlm.nih.gov/clinvar/variation/1343799/) |

**All HGVS expressions:** `NC_000001.10:g.228285560C>G`, `NC_000001.11:g.228097859C>G`, `NM_001024226.2:c.392C>G`, `NM_001024227.1:c.392C>G`, `NM_001024228.2:c.392C>G`, `NM_001658.4:c.392C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9416) — concordant with the pathogenic call
- REVEL 0.719 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.905 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.641, GERP 1.86, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.4**. 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 0.33** across the covering region of the MANE Select transcript (228,097,428–228,098,010), spanning 582 bp — the region is depleted of missense variation. Chi-square p 9.3e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ARF1** population constraint: LOEUF 0.247, pLI 0.99953, missense-Z 4.1558. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **periventricular nodular heterotopia** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.93, 57% of residues very-high.

**40 experimental structure(s)** (PDB): [1HUR](https://www.rcsb.org/structure/1HUR), [1RE0](https://www.rcsb.org/structure/1RE0), [1U81](https://www.rcsb.org/structure/1U81), [3O47](https://www.rcsb.org/structure/3O47), [4HMY](https://www.rcsb.org/structure/4HMY), [6CM9](https://www.rcsb.org/structure/6CM9) — incl. mutant structure 6D83.

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

*Describes the biological roles of ARF1 (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:** ARF1's established molecular role includes RNA binding. In Reactome, ARF1 is annotated in disease pathway(s) including **Nef Mediated CD4 Down-regulation**.

**Disease mechanism (Reactome):** ARF1 loss or alteration is curated in [Nef Mediated CD4 Down-regulation](https://reactome.org/content/detail/R-HSA-167590).

### Pathways affected {#pathways}

ARF1 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nef Mediated CD4 Down-regulation](https://reactome.org/content/detail/R-HSA-167590) | 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 |
| [Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation](https://reactome.org/content/detail/R-HSA-8950505) | curated |
| [Glycosphingolipid transport](https://reactome.org/content/detail/R-HSA-9845576) | curated |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | curated |
| [Intra-Golgi traffic](https://reactome.org/content/detail/R-HSA-6811438) | curated |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Synthesis of PIPs at the Golgi membrane](https://reactome.org/content/detail/R-HSA-1660514) | curated |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | curated |
| [trans-Golgi Network Vesicle Budding](https://reactome.org/content/detail/R-HSA-199992) | curated |

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

**Molecular function:** RNA binding, GTPase activity, protein domain specific binding.

**Biological process:** intracellular copper ion homeostasis, cellular response to virus.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-12.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Groupe Hospitalier Pitie Salpetriere, Uf Genomique Du Developpement, Assistance Publique Hopitaux de Paris Sorbonne Université | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-12 |

## Associated conditions {#conditions}

[periventricular nodular heterotopia 8](https://sugi.bio/atlas/disease/periventricular-nodular-heterotopia-8/).

**Reported phenotype names (ClinVar):** Periventricular nodular heterotopia 8.

## Similar variants {#similar}

Related ARF1 variant pages (same residue, condition, or type): [ARF1 p.Pro131Leu](/variant/arf1-p-pro131leu), [ARF1 p.Pro131Ser](/variant/arf1-p-pro131ser), [ARF1 p.Arg19Cys](/variant/arf1-p-arg19cys), [ARF1 p.Arg99His](/variant/arf1-p-arg99his), [ARF1 p.Gly70Ser](/variant/arf1-p-gly70ser), [ARF1 p.Thr48Ile](/variant/arf1-p-thr48ile), [ARF1 p.Tyr35Asp](/variant/arf1-p-tyr35asp), [ARF1 p.Arg99Cys](/variant/arf1-p-arg99cys).

### 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 1343799). 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.*