Is ACE p.Ala731= (c.2193A>G) pathogenic?

ACE p.Ala731= (c.2193A>G) is classified Benign in ACE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 65%, eas) — too common for a highly-penetrant pathogenic allele; Associated with renal tubular dysgenesis.

What condition is associated with ACE p.Ala731= (c.2193A>G)?

ACE p.Ala731= (c.2193A>G) is associated with renal tubular dysgenesis (ClinVar).

ACE p.Ala731=

Q: How common is ACE p.Ala731= (c.2193A>G) in the general population?

ACE p.Ala731= (c.2193A>G) is common (popmax 65%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2193A>G · rs4331 · VCV256800

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 65%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

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 -8.3	GERP -3.1
Overall
CADD	0.222	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 65% East Asian · 29,185/44,866 alleles

Filtering AF 64.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 64.2%

Overall 47.8% 771,468/1,613,954 alleles · common exomes 700,987/1,461,760 · genomes 70,481/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	65%	2
South Asian	58.1%	2
Admixed American	56.1%	2
Remaining individualsnot grpmax-eligible	47%	2
European (non-Finnish)	46.9%	2
Finnishnot grpmax-eligible	44.5%	2
Amishnot grpmax-eligible	41.6%	2
African / African-American	41.3%	2
Ashkenazi Jewishnot grpmax-eligible	36.5%	3
Middle Eastern	36%	3

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.Ala731=
Coding: c.2193A>G
MANE Select: NM_000789
dbSNP: rs4331
Type: single nucleotide variant
Location: chr17:63486691 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 731: an α-helix; the peptidase m2 2 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

Similar variants

ACE p.Ala731Val 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
ACE c.2739+5G>A Uncertain significance ★★ 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-ala731 (accessed [today's date]).

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