Is RANGRF p.Leu165= (c.493C>T) pathogenic?

RANGRF p.Leu165= (c.493C>T) is classified Likely benign in RANGRF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). Very rare (popmax 0.00667%, amr); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.Leu165= (c.493C>T)?

RANGRF p.Leu165= (c.493C>T) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.Leu165= (c.493C>T) in the general population?

RANGRF p.Leu165= (c.493C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

RANGRF p.Leu165=

c.493C>T · rs755816071 · VCV1110141

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

cardiac rhythm disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP -2.1, phastCons 1
Overall
CADD	11.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,992 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000496% 8/1,613,994 alleles · very rare exomes 4/1,461,874 · genomes 4/152,120 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,998
African / African-American	0.00534%	18,718

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.Leu165=
Coding: c.493C>T
MANE Select: NM_016492
dbSNP: rs755816071
Type: single nucleotide variant
Location: chr17:8289868 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 165: 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)

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.Leu165Pro Uncertain significance ★ ⚠ same residue
RANGRF p.Leu165Met Uncertain significance ★ ⚠ same residue
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

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-leu165 (accessed [today's date]).

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