Is RANGRF p.Ala119Glu (c.356C>A) pathogenic?

RANGRF p.Ala119Glu (c.356C>A) is classified Uncertain significance in RANGRF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.14); Ultra-rare (popmax 0.025%, amr); Associated with cardiac rhythm disease.

What condition is associated with RANGRF p.Ala119Glu (c.356C>A)?

RANGRF p.Ala119Glu (c.356C>A) is associated with cardiac rhythm disease (ClinVar).

How common is RANGRF p.Ala119Glu (c.356C>A) in the general population?

RANGRF p.Ala119Glu (c.356C>A) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about RANGRF p.Ala119Glu (c.356C>A)?

AlphaMissense predicts likely benign (score 0.14) — an in-silico prediction, not a clinical call.

RANGRF p.Ala119Glu

c.356C>A · rs371382956 · VCV2965903

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.14 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiac rhythm disease

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.14	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,144 bp · p 0.49 · regional, not allelic
Overall
CADD	21.2	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 0.025% Admixed American · 15/60,000 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00186% 30/1,614,056 alleles · ultra-rare exomes 20/1,461,888 · genomes 10/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,000
European (non-Finnish)	0.00127%	78,670

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.Ala119Glu
Coding: c.356C>A
MANE Select: NM_016492
dbSNP: rs371382956
Type: single nucleotide variant
Location: chr17:8289507 (GRCh38)

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

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-ala119glu (accessed [today's date]).

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