Is RANGRF p.Leu9= (c.27G>C) pathogenic?

RANGRF p.Leu9= (c.27G>C) is classified Likely benign in RANGRF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). Rare (popmax 0.345%, mid); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.Leu9= (c.27G>C)?

RANGRF p.Leu9= (c.27G>C) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.Leu9= (c.27G>C) in the general population?

RANGRF p.Leu9= (c.27G>C) is rare (popmax 0.345%, mid) (gnomAD).

RANGRF p.Leu9=

c.27G>C · rs200305092 · VCV392818

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.345%, mid)

Conditions

cardiac rhythm disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.4, phastCons 1
Overall
CADD	3.561	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.345% Middle Eastern · 21/6,084 alleles

Filtering AF 0.231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.194%

Overall 0.0105% 170/1,614,076 alleles · rare exomes 159/1,461,830 · genomes 11/152,246 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.345%	290
South Asian	0.0263%	3,795
Remaining individualsnot grpmax-eligible	0.024%	4,166
European (non-Finnish)	0.00924%	10,826
African / African-American	0.00133%	74,948

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.Leu9=
Coding: c.27G>C
MANE Select: NM_016492
dbSNP: rs200305092
Type: single nucleotide variant
Location: chr17:8288815 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 9: a β-strand

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-leu9 (accessed [today's date]).

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