Is RANGRF p.Arg65Leu (c.194G>T) pathogenic?

RANGRF p.Arg65Leu (c.194G>T) is classified Uncertain significance in RANGRF (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-19). AlphaMissense: likely benign (0.1866); Very rare (popmax 0.00133%, afr); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.Arg65Leu (c.194G>T)?

RANGRF p.Arg65Leu (c.194G>T) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.Arg65Leu (c.194G>T) in the general population?

RANGRF p.Arg65Leu (c.194G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RANGRF p.Arg65Leu (c.194G>T)?

AlphaMissense predicts likely benign (score 0.1866) — an in-silico prediction, not a clinical call.

RANGRF p.Arg65Leu

c.194G>T · rs1478013092 · VCV841681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiac rhythm disease

Computational evidence

Protein change
AlphaMissense	0.1866	likely benign
REVEL	0.613	indeterminate
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.56	donor loss · deltas
Pangolin	Δ0.64	loss · gain 0.31 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,144 bp · p 0.49 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00133% African / African-American · 1/75,070 alleles

Overall 6.2e-05% 1/1,613,404 alleles · very rare exomes 1/1,461,036 · genomes 0/152,368 · 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.Arg65Leu
Coding: c.194G>T
MANE Select: NM_016492
dbSNP: rs1478013092
Type: single nucleotide variant
Location: chr17:8289072 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 65: the 'interaction with ran' region; 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 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-arg65leu (accessed [today's date]).

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