# NM_016492.5(RANGRF):c.484C>T (p.Pro162Ser)

https://sugi.bio/variant/rangrf-p-pro162ser

## Summary

**RANGRF p.Pro162Ser (c.484C>T)** is classified **Uncertain significance** in RANGRF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.0033%, nfe); Associated with cardiac rhythm disease.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1246808833 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0033%, 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 2 submitters, 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.Pro162Ser |
| Coding change (HGVS c.) | c.484C>T |
| MANE Select transcript | [NM_016492](https://www.ncbi.nlm.nih.gov/nuccore/NM_016492) |
| dbSNP | [rs1246808833](https://www.ncbi.nlm.nih.gov/snp/rs1246808833/) |
| Variant type | single nucleotide variant |
| Location | chr17:8289859-8289859 (GRCh38) |
| ClinVar | [VCV3008964](https://www.ncbi.nlm.nih.gov/clinvar/variation/3008964/) |

**All HGVS expressions:** `NC_000017.10:g.8193177C>T`, `NC_000017.11:g.8289859C>T`, `NG_028189.1:g.6209C>T`, `NM_001177801.2:c.*267C>T`, `NM_001177802.2:c.*298C>T`, `NM_001320871.2:c.855G>A`, `NM_001320872.2:c.855G>A`, `NM_001330127.2:c.*41C>T`, `NM_016492.5:c.484C>T`, `NM_201520.3:c.855G>A`, `NR_135483.2:n.1512G>A`, `NR_135484.2:n.1524G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0828)
- REVEL 0.117 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.811 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.757, GERP 0.425, phastCons 0.892 — weakly conserved position
- CADD: **PHRED 14.28**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.29 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.*
- Pangolin: Δ**0.32** (gain), gain 0.32 / loss 0.00. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0033%** (nfe) · FAF95 0.00247% · FAF99 0.00217% · 39/1,180,044 in the highest group · 40/1,614,038 alleles overall — very rare (popmax 0.0033%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0033% | 30,258 |
| Admixed American | 0.00167% | 59,996 |

*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 **162** lies in an α-helix; 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiac arrhythmia, not specified, AllHighlyPenetrant, Cardiac rhythm disease, Arrhythmia.

## 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.Ser84Ala](/variant/rangrf-p-ser84ala), [RANGRF p.Val122Met](/variant/rangrf-p-val122met), [RANGRF p.Val58Leu](/variant/rangrf-p-val58leu).

### 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 3008964). 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.*