# NM_016492.5(RANGRF):c.437delC (p.Pro147fs)

https://sugi.bio/variant/rangrf-p-pro147fs

## Summary

**RANGRF p.Pro147fs (c.437delC)** is classified **Uncertain significance** in RANGRF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). Very rare (popmax 0.000424%, nfe); Associated with cardiac rhythm disease.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2151610404 · 1 submitter · 1 linked condition · very rare (popmax 0.000424%, 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.Pro147fs |
| Coding change (HGVS c.) | c.437delC |
| MANE Select transcript | [NM_016492](https://www.ncbi.nlm.nih.gov/nuccore/NM_016492) |
| dbSNP | [rs2151610404](https://www.ncbi.nlm.nih.gov/snp/rs2151610404/) |
| Variant type | Deletion |
| Location | chr17:8289584-8289584 (GRCh38) |
| ClinVar | [VCV1522246](https://www.ncbi.nlm.nih.gov/clinvar/variation/1522246/) |

**All HGVS expressions:** `NC_000017.10:g.8192906del`, `NC_000017.11:g.8289588del`, `NG_028189.1:g.5938del`, `NM_001177801.2:c.437del`, `NM_001177802.2:c.*27del`, `NM_001320871.2:c.*32del`, `NM_001320872.2:c.*32del`, `NM_001330127.2:c.351+174del`, `NM_016492.5:c.437delC`, `NM_201520.3:c.*32del`, `NR_135483.2:n.1577del`, `NR_135484.2:n.1589del`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.117, GERP -5.06, phastCons 0.777 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.107, pLI 3.8612e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (4 of 5, 4 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,178,692 in the highest group · 5/1,612,528 alleles overall — very rare (popmax 0.000424%, 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 **147** lies in a UniProt-annotated variant site (found in patients with cardiac arrhythmias including brugada syndrome; uncertain significance; loss of function in enhancing the expression of scn5a at the cell membrane).

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.


### 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 2022-08-23.

**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 | 2022-08-23 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related RANGRF variant pages (same residue, condition, or type): [RANGRF p.Pro147Arg](/variant/rangrf-p-pro147arg), [RANGRF c.351+4_351+19del](/variant/rangrf-c-351-plus-4-351-plus-19del), [RANGRF p.Leu124del](/variant/rangrf-p-leu124del), [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), [RANGRF p.Asp6fs](/variant/rangrf-p-asp6fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1522246). 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.*