# NM_016492.5(RANGRF):c.176G>C (p.Arg59Pro)

https://sugi.bio/variant/rangrf-p-arg59pro

## Summary

**RANGRF p.Arg59Pro (c.176G>C)** is classified **Uncertain significance** in RANGRF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.1024); Very rare (popmax 0.00161%, nfe); Associated with cardiac rhythm disease.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750625803 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00161%, nfe)

## For patients & families {#patients}

This is a change in the RANGRF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to cardiac rhythm disease.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 271 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RANGRF](https://sugi.bio/atlas/gene/RANGRF/) |
| Protein change (HGVS p.) | p.Arg59Pro |
| Coding change (HGVS c.) | c.176G>C |
| MANE Select transcript | [NM_016492](https://www.ncbi.nlm.nih.gov/nuccore/NM_016492) |
| dbSNP | [rs750625803](https://www.ncbi.nlm.nih.gov/snp/rs750625803/) |
| Variant type | single nucleotide variant |
| Location | chr17:8289054-8289054 (GRCh38) |
| ClinVar | [VCV1403512](https://www.ncbi.nlm.nih.gov/clinvar/variation/1403512/) |

**All HGVS expressions:** `NC_000017.10:g.8192372G>C`, `NC_000017.11:g.8289054G>C`, `NG_028189.1:g.5404G>C`, `NG_194662.1:g.232G>C`, `NG_194663.1:g.32G>C`, `NM_001177801.2:c.176G>C`, `NM_001177802.2:c.176G>C`, `NM_001320871.2:c.*42+520C>G`, `NM_001320872.2:c.*429C>G`, `NM_001330127.2:c.176G>C`, `NM_016492.5:c.176G>C`, `NM_201520.3:c.*562C>G`, `NR_135483.2:n.2107C>G`, `NR_135484.2:n.1943C>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** (0.1024)
- REVEL 0.201 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.776 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.40) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.178, GERP -5.34 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.04**. 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 0.96** across the covering region of the MANE Select transcript (8,288,789–8,289,933), spanning 1,144 bp. Chi-square p 0.49. 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 **0.40**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00161%** (nfe) · FAF95 0.00103% · FAF99 0.00083% · 19/1,179,970 in the highest group · 19/1,613,746 alleles overall — very rare (popmax 0.00161%, nfe).

*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}

**RANGRF** population constraint: LOEUF 1.107, pLI 3.8612e-05, missense-Z 0.63269. *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):

- **Brugada syndrome** — Refuted (AD)

## Protein context {#protein}

Residue **59** lies in the 'interaction with ran' region.

AlphaFold model confidence (whole protein): pLDDT 78.36, 13% of residues very-high.

**1 experimental structure(s)** (PDB): [5YFG](https://www.rcsb.org/structure/5YFG).

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

*Describes the biological roles of RANGRF (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:** RANGRF's established molecular role includes sodium channel regulator activity. p.Arg59Pro falls in the interaction with ran region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |

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

**Molecular function:** sodium channel regulator activity, small GTPase binding, transmembrane transporter binding, channel activator activity.

**Biological process:** regulation of membrane depolarization, endoplasmic reticulum to Golgi vesicle-mediated transport, obsolete protein exit from endoplasmic reticulum, mitotic spindle assembly, regulation of bundle of His cell action potential, regulation of cardiac muscle cell action potential involved in regulation of contraction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-25 |

## Associated conditions {#conditions}

[cardiac rhythm disease](https://sugi.bio/atlas/disease/cardiac-rhythm-disease/).

**Reported phenotype names (ClinVar):** Cardiac arrhythmia, Cardiac rhythm disease, Arrhythmia.

## Similar variants {#similar}

Related RANGRF variant pages (same residue, condition, or type): [RANGRF p.Arg59Gly](/variant/rangrf-p-arg59gly), [RANGRF p.Arg59Leu](/variant/rangrf-p-arg59leu), [RANGRF p.Arg59Trp](/variant/rangrf-p-arg59trp), [RANGRF p.Arg59=](/variant/rangrf-p-arg59), [RANGRF c.77+5G>A](/variant/rangrf-c-77-plus-5g-a), [RANGRF p.Ala56Val](/variant/rangrf-p-ala56val), [RANGRF p.Arg130Lys](/variant/rangrf-p-arg130lys), [RANGRF p.Asp179Asn](/variant/rangrf-p-asp179asn).

### 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 1403512). 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.*