Is ACE p.Arg409= (c.1227T>C) pathogenic?

ACE p.Arg409= (c.1227T>C) is classified Conflicting classifications of pathogenicity in ACE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-08-10). Very rare (popmax 0.00333%, amr); Associated with microvascular complications of diabetes, susceptibility to, 3.

What condition is associated with ACE p.Arg409= (c.1227T>C)?

ACE p.Arg409= (c.1227T>C) is associated with microvascular complications of diabetes, susceptibility to, 3, renal tubular dysgenesis of genetic origin, renal tubular dysgenesis (ClinVar).

How common is ACE p.Arg409= (c.1227T>C) in the general population?

ACE p.Arg409= (c.1227T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

ACE p.Arg409=

c.1227T>C · rs373568007 · VCV324376

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

microvascular complications of diabetes, susceptibility to, 3

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 -0.78	GERP -2.9
Overall
CADD	1.311	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00254% 41/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed Americangrpmax	0.00333%	30,004
European (non-Finnish)	0.000339%	295,004

Ashkenazi Jewish 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: ACE
Protein: p.Arg409=
Coding: c.1227T>C
MANE Select: NM_000789
dbSNP: rs373568007
Type: single nucleotide variant
Location: chr17:63482574 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 409: the peptidase m2 1 domain

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

Disease context

microvascular complications of diabetes, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal tubular dysgenesis of genetic origin renal tubular dysgenesis hemorrhage, intracerebral, susceptibility to

Similar variants

ACE p.Arg409Cys Uncertain significance ★ ⚠ same residue
ACE p.Arg409Leu Uncertain significance ★ ⚠ same residue
ACE c.1342+1G>T Likely pathogenic ★★ same condition
ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same condition
ACE c.3503+1G>C Likely pathogenic ★★ same condition
ACE c.945+2T>G Likely pathogenic ★★ same condition
ACE p.Arg265Ter Pathogenic ★★ same condition
ACE p.Arg496Ter 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-arg409 (accessed [today's date]).

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