Is RNF213 p.Pro3759= (c.11277G>A) pathogenic?

RNF213 p.Pro3759= (c.11277G>A) is classified Benign in RNF213 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Common (popmax 8.55%, mid) — too common for a highly-penetrant pathogenic allele.

RNF213 p.Pro3759=

Q: How common is RNF213 p.Pro3759= (c.11277G>A) in the general population?

RNF213 p.Pro3759= (c.11277G>A) is common (popmax 8.55%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.11277G>A · rs61741791 · VCV1629047

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 8.55%, mid) — too common for a highly-penetrant pathogenic allele

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 1.1	GERP 0.65, phastCons 0.001
Overall
CADD	6.526	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.55% Middle Eastern · 518/6,058 alleles

Filtering AF 7.94% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.7%

Overall 4.89% 78,910/1,613,880 alleles · common exomes 71,902/1,461,572 · genomes 7,008/152,308 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	15.7%	6
Ashkenazi Jewishnot grpmax-eligible	9.48%	11
Middle Easterngrpmax	8.55%	12
South Asian	6.41%	16
Remaining individualsnot grpmax-eligible	4.96%	20
European (non-Finnish)	4.89%	20
Finnishnot grpmax-eligible	4.38%	23
Admixed American	3.42%	29
African / African-American	3.38%	30
East Asian	3.05%	33

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro3759=
Coding: c.11277G>A
MANE Select: NM_001256071
dbSNP: rs61741791
Type: single nucleotide variant
Location: chr17:80361810 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 3759: an α-helix

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

Similar variants

RNF213 p.Ala5114Thr Uncertain significance ★★ ⚠ same type
RNF213 p.Arg2727Gly Uncertain significance ★★ ⚠ same type
RNF213 p.Arg3585His Uncertain significance ★★ ⚠ same type
RNF213 p.Arg4276Trp Uncertain significance ★★ ⚠ same type
RNF213 p.Arg4492Gln Uncertain significance ★★ ⚠ same type
RNF213 p.Arg4810Ser Uncertain significance ★★ ⚠ same type
RNF213 p.Arg4958Trp Uncertain significance ★★ ⚠ same type
RNF213 p.Asn1439Ser Uncertain significance ★★ ⚠ same type

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-pro3759 (accessed [today's date]).

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