Is RANGRF p.His178= (c.534C>T) pathogenic?

RANGRF p.His178= (c.534C>T) is classified Likely benign in RANGRF (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00229%, nfe); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.His178= (c.534C>T)?

RANGRF p.His178= (c.534C>T) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.His178= (c.534C>T) in the general population?

RANGRF p.His178= (c.534C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

RANGRF p.His178=

c.534C>T · rs746275946 · VCV1561897

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Conditions

cardiac rhythm disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.227	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -4.8
Overall
CADD	3.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,180,030 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00173% 28/1,614,156 alleles · very rare exomes 28/1,461,878 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,705
African / African-American	0.00133%	75,030

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.His178=
Coding: c.534C>T
MANE Select: NM_016492
dbSNP: rs746275946
Type: single nucleotide variant
Location: chr17:8289909 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 178: 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.His178Gln 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
RANGRF p.Ser84Ala 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-his178 (accessed [today's date]).

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