Is ACE p.Arg228Cys (c.682C>T) pathogenic?

ACE p.Arg228Cys (c.682C>T) is classified Conflicting classifications of pathogenicity in ACE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-07-30). AlphaMissense: likely benign (0.3016); Ultra-rare (popmax 0.0751%, nfe); Associated with renal tubular dysgenesis.

How common is ACE p.Arg228Cys (c.682C>T) in the general population?

ACE p.Arg228Cys (c.682C>T) is ultra-rare (popmax 0.0751%, nfe) (gnomAD).

What do computational predictors say about ACE p.Arg228Cys (c.682C>T)?

AlphaMissense predicts likely benign (score 0.3016) — an in-silico prediction, not a clinical call.

ACE p.Arg228Cys

Q: What condition is associated with ACE p.Arg228Cys (c.682C>T)?

ACE p.Arg228Cys (c.682C>T) is associated with renal tubular dysgenesis, renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3 (ClinVar).

c.682C>T · rs141543325 · VCV324367

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3016 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0751%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal tubular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.3016	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -14.94	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.75, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0751% European (non-Finnish) · 886/1,180,024 alleles

Filtering AF 0.071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0693%

Overall 0.0587% 947/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0751%	1,332
Remaining individualsnot grpmax-eligible	0.0512%	1,953
Middle Eastern	0.033%	3,031
Admixed American	0.03%	3,335
African / African-American	0.00933%	10,722
East Asian	0.00223%	44,882
South Asian	0.0011%	91,084

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.Arg228Cys
Coding: c.682C>T
MANE Select: NM_000789
dbSNP: rs141543325
Type: single nucleotide variant
Location: chr17:63480363 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 228: an α-helix; the peptidase m2 1 domain

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

Disease context

renal tubular dysgenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal tubular dysgenesis of genetic origin microvascular complications of diabetes, susceptibility to, 3 hemorrhage, intracerebral, susceptibility to

Similar variants

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
ACE p.Arg508Ter Pathogenic ★★ same condition
ACE p.Arg791Ter 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-arg228cys (accessed [today's date]).

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