# NM_015193.5(ARC):c.1155C>G (p.Ser385Arg)

https://sugi.bio/variant/arc-p-ser385arg

## Summary

**ARC p.Ser385Arg (c.1155C>G)** is classified **Uncertain significance** in ARC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1727); No allele count reported in gnomAD v4.1 (AN 1,569,744).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,569,744)

## For patients & families {#patients}

This is a change in the ARC 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 | [ARC](https://sugi.bio/atlas/gene/ARC/) |
| Protein change (HGVS p.) | p.Ser385Arg |
| Coding change (HGVS c.) | c.1155C>G |
| MANE Select transcript | [NM_015193](https://www.ncbi.nlm.nih.gov/nuccore/NM_015193) |
| Variant type | single nucleotide variant |
| Location | chr8:142613117-142613117 (GRCh38) |
| ClinVar | [VCV3936314](https://www.ncbi.nlm.nih.gov/clinvar/variation/3936314/) |

**All HGVS expressions:** `NC_000008.10:g.143694478G>C`, `NC_000008.11:g.142613117G>C`, `NM_001412852.1:c.1155C>G`, `NM_015193.5:c.1155C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1727)
- REVEL 0.01 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.793 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.39, GERP -3.16 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.03**. 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 1.21** across the covering region of the MANE Select transcript (142,613,084–142,613,202), spanning 118 bp. Chi-square p 0.1. 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>A, Δ0.27 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: **no allele count reported in gnomAD v4.1 (AN 1,569,744)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ARC** population constraint: LOEUF 1.393, pLI 0.00081608, missense-Z 0.32399. *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 **385** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 66.72, 10% of residues very-high.

**11 experimental structure(s)** (PDB): [6TN7](https://www.rcsb.org/structure/6TN7), [6TNQ](https://www.rcsb.org/structure/6TNQ), [6TQ0](https://www.rcsb.org/structure/6TQ0), [6YTU](https://www.rcsb.org/structure/6YTU), [7R1Z](https://www.rcsb.org/structure/7R1Z), [7R23](https://www.rcsb.org/structure/7R23) — incl. mutant structure 26AP.

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

*Describes the biological roles of ARC (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:** ARC's established molecular role includes mRNA binding. p.Ser385Arg falls in the disordered region.


### Pathways affected {#pathways}

ARC participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NGF-stimulated transcription](https://reactome.org/content/detail/R-HSA-9031628) | electronic |

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

**Molecular function:** mRNA binding, structural molecule activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-07.

**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 | 2025-05-07 |

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

## Similar variants {#similar}

Related ARC variant pages (same residue, condition, or type): [ARC c.*258C>T](/variant/arc-c-star-258c-t), [ARC p.Ala144Ser](/variant/arc-p-ala144ser), [ARC p.Arg107Cys](/variant/arc-p-arg107cys), [ARC p.Arg129His](/variant/arc-p-arg129his), [ARC p.Arg304His](/variant/arc-p-arg304his), [ARC p.Arg335Cys](/variant/arc-p-arg335cys), [ARC p.Arg392Gln](/variant/arc-p-arg392gln), [ARC p.Asp307Glu](/variant/arc-p-asp307glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3936314). 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.*