# NM_016492.5(RANGRF):c.465C>T (p.Pro155=)

https://sugi.bio/variant/rangrf-p-pro155

## Summary

**RANGRF p.Pro155= (c.465C>T)** is classified **Likely benign** in RANGRF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). Very rare (popmax 0.00729%, nfe); Associated with cardiac rhythm disease.

**At a glance:** Likely benign · review: Single submitter · rsID rs762346321 · 1 submitter · 1 linked condition · very rare (popmax 0.00729%, nfe)

## For patients & families {#patients}

This is a change in the RANGRF gene that is classified as likely benign — not considered disease-causing, 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.Pro155= |
| Coding change (HGVS c.) | c.465C>T |
| MANE Select transcript | [NM_016492](https://www.ncbi.nlm.nih.gov/nuccore/NM_016492) |
| dbSNP | [rs762346321](https://www.ncbi.nlm.nih.gov/snp/rs762346321/) |
| Variant type | single nucleotide variant |
| Location | chr17:8289840-8289840 (GRCh38) |
| ClinVar | [VCV1147208](https://www.ncbi.nlm.nih.gov/clinvar/variation/1147208/) |

**All HGVS expressions:** `NC_000017.10:g.8193158C>T`, `NC_000017.11:g.8289840C>T`, `NG_028189.1:g.6190C>T`, `NM_001177801.2:c.*248C>T`, `NM_001177802.2:c.*279C>T`, `NM_001320871.2:c.860+14G>A`, `NM_001320872.2:c.860+14G>A`, `NM_001330127.2:c.*22C>T`, `NM_016492.5:c.465C>T`, `NM_201520.3:c.860+14G>A`

## 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 2.561, GERP 0.499, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.31**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.44 acceptor 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 (gnomAD v4.1): grpmax **0.00729%** (nfe) · FAF95 0.00604% · FAF99 0.00557% · 86/1,180,052 in the highest group · 93/1,613,988 alleles overall — very rare (popmax 0.00729%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00729% | 13,722 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| African / African-American | 0.00267% | 37,449 |
| East Asian | 0.00223% | 44,896 |
| Admixed American | 0.00167% | 59,990 |

*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 **155** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-07 |

## 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 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.His81Arg](/variant/rangrf-p-his81arg), [RANGRF p.Pro162Ser](/variant/rangrf-p-pro162ser), [RANGRF p.Ser84Ala](/variant/rangrf-p-ser84ala), [RANGRF p.Val122Met](/variant/rangrf-p-val122met).

### 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 1147208). 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.*