Is RANGRF p.Leu129= (c.387G>A) pathogenic?

RANGRF p.Leu129= (c.387G>A) is classified Likely benign in RANGRF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-13). Very rare (popmax 8.47e-05%, nfe); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.Leu129= (c.387G>A)?

RANGRF p.Leu129= (c.387G>A) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.Leu129= (c.387G>A) in the general population?

RANGRF p.Leu129= (c.387G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

RANGRF p.Leu129=

c.387G>A · rs2151610308 · VCV1608663

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

cardiac rhythm disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.108	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.28	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1.2	GERP -4.6, phastCons 1
Overall
CADD	6.468	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,174 alleles · very rare exomes 1/1,461,874 · genomes 0/152,300 · joint denominator

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.Leu129=
Coding: c.387G>A
MANE Select: NM_016492
dbSNP: rs2151610308
Type: single nucleotide variant
Location: chr17:8289538 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 129: 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 c.77+5G>A Uncertain significance ★★ same condition
RANGRF p.Ala56Val Uncertain significance ★★ ⚠ same condition
RANGRF p.Arg130Lys 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-leu129 (accessed [today's date]).

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