Is RANGRF p.Arg130Lys (c.389G>A) pathogenic?

RANGRF p.Arg130Lys (c.389G>A) is classified Uncertain significance in RANGRF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.635); Very rare (popmax 0.008%, afr); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.Arg130Lys (c.389G>A)?

RANGRF p.Arg130Lys (c.389G>A) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.Arg130Lys (c.389G>A) in the general population?

RANGRF p.Arg130Lys (c.389G>A) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about RANGRF p.Arg130Lys (c.389G>A)?

AlphaMissense predicts likely pathogenic (score 0.635) — an in-silico prediction, not a clinical call.

RANGRF p.Arg130Lys

c.389G>A · rs546562640 · VCV646452

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiac rhythm disease

Computational evidence

Protein change
AlphaMissense	0.635	likely pathogenic
REVEL	0.629	indeterminate
SaProt	LLR -10.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,144 bp · p 0.49 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.008% African / African-American · 6/75,040 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000434% 7/1,614,166 alleles · very rare exomes 5/1,461,878 · genomes 2/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,507
European (non-Finnish)	8.47e-05%	1,180,022

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RANGRF
Protein: p.Arg130Lys
Coding: c.389G>A
MANE Select: NM_016492
dbSNP: rs546562640
Type: single nucleotide variant
Location: chr17:8289540 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 130: a β-strand; 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)

Full RANGRF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiac rhythm disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RANGRF p.Arg130= Likely benign ★ same residue
RANGRF c.77+5G>A Uncertain significance ★★ same condition
RANGRF p.Ala56Val Uncertain significance ★★ ⚠ same condition
RANGRF p.Asp179Asn Uncertain significance ★★ ⚠ same condition
RANGRF p.His81Arg Uncertain significance ★★ ⚠ same condition
RANGRF p.Pro162Ser Uncertain significance ★★ ⚠ same condition
RANGRF p.Ser84Ala Uncertain significance ★★ ⚠ same condition
RANGRF p.Val122Met Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rangrf-p-arg130lys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown