Is RNF213 p.Ala4530= (c.13590G>A) pathogenic?

RNF213 p.Ala4530= (c.13590G>A) is classified Benign/Likely benign in RNF213 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-25). Common (popmax 5.35%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Moyamoya disease 2.

What condition is associated with RNF213 p.Ala4530= (c.13590G>A)?

RNF213 p.Ala4530= (c.13590G>A) is associated with Moyamoya disease 2 (ClinVar).

How is Moyamoya disease inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

RNF213 p.Ala4530=

Q: How common is RNF213 p.Ala4530= (c.13590G>A) in the general population?

RNF213 p.Ala4530= (c.13590G>A) is common (popmax 5.35%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.13590G>A · rs61739536 · VCV781335

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.35%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Moyamoya disease 2

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 -3.9	GERP -3.2
Overall
CADD	0.295	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.35% African / African-American · 4,019/75,062 alleles

Filtering AF 5.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.16%

Overall 0.288% 4,654/1,614,216 alleles · common exomes 2,296/1,461,880 · genomes 2,358/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.35%	19
Admixed American	0.4%	250
Remaining individualsnot grpmax-eligible	0.386%	259
Middle Eastern	0.347%	289
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
South Asian	0.022%	4,554
European (non-Finnish)	0.0089%	11,238

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: RNF213
Protein: p.Ala4530=
Coding: c.13590G>A
MANE Select: NM_001256071
dbSNP: rs61739536
Type: single nucleotide variant
Location: chr17:80379664 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)

Full RNF213 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Moyamoya disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Moyamoya disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Multigenic/multifactorial
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

RNF213 p.Ala4530Val Likely benign ★ same residue
RNF213 p.Arg4276Trp Uncertain significance ★★ ⚠ same condition
RNF213 p.Asn1439Ser Uncertain significance ★★ ⚠ same condition
RNF213 p.Val3974Met Uncertain significance ★★ same condition
RNF213 c.10727-4A>G Benign/Likely benign ★★ same condition
RNF213 p.Ala1135Val Benign/Likely benign ★★ same condition
RNF213 p.Ala1844Thr Likely benign ★★ same condition
RNF213 p.Ala370= Benign/Likely benign ★★ 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/rnf213-p-ala4530 (accessed [today's date]).

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