Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.235%, afr)
Conditions
1
renal tubular dysgenesis
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 1.3 | GERP 0.16, phastCons 1 |
| Overall | ||
| CADD | 11.43 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.235%
African / African-American · 175/74,332 alleles
Filtering AF
0.207%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.196%
Overall
0.0131%
208/1,582,346 alleles · rare
exomes 94/1,429,986 · genomes 114/152,360 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.235% | 425 |
| Admixed American | 0.0269% | 3,715 |
| Remaining individualsnot grpmax-eligible | 0.0229% | 4,376 |
| European (non-Finnish) | 0.000344% | 291,060 |
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
- ACE
- Protein
- p.Arg137=
- Coding
- c.411G>T
- MANE Select
- NM_000789
- dbSNP
- rs3729659
- Type
- single nucleotide variant
- Location
- chr17:63478092 (GRCh38)
- Gene constraint
- LOEUF 0.88 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 91.38 · 97 PDB
- Residue 137
- an α-helix; the peptidase m2 1 domain
Similar variants
- ACE p.Arg137Gln Uncertain significance ★ ⚠ same residue
- ACE p.Arg137Trp Uncertain significance ★ ⚠ same residue
- ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same condition
- ACE c.3503+1G>C Likely pathogenic ★★ same condition
- ACE p.Arg496Ter Pathogenic/Likely pathogenic ★★ same condition
- ACE p.Arg508Ter Pathogenic ★★ same condition
- ACE p.Arg791Ter Pathogenic ★★ same condition
- ACE p.Tyr266Ter Pathogenic/Likely pathogenic ★★ 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/ace-p-arg137 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown