Is RNF213 p.Pro74= (c.222C>T) pathogenic?

RNF213 p.Pro74= (c.222C>T) is classified Benign in RNF213 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-25). Common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele.

RNF213 p.Pro74=

Q: How common is RNF213 p.Pro74= (c.222C>T) in the general population?

RNF213 p.Pro74= (c.222C>T) is common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.222C>T · rs60826056 · VCV1598585

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 12.2%, afr) — 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -2.8
Overall
CADD	0.854	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.2% African / African-American · 9,148/74,960 alleles

Filtering AF 12% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.9%

Overall 0.64% 10,321/1,613,196 alleles · common exomes 5,098/1,461,032 · genomes 5,223/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.2%	8
Remaining individualsnot grpmax-eligible	0.76%	132
Admixed American	0.715%	140
Middle Eastern	0.365%	274
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700
European (non-Finnish)	0.0194%	5,153
South Asian	0.00988%	10,120
East Asian	0.00223%	44,864

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.Pro74=
Coding: c.222C>T
MANE Select: NM_001256071
dbSNP: rs60826056
Type: single nucleotide variant
Location: chr17:80273365 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 74: the 'disordered' region

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-pro74 (accessed [today's date]).

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