Is ACE p.Ile75Val (c.223A>G) pathogenic?

ACE p.Ile75Val (c.223A>G) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-04). AlphaMissense: likely benign (0.1701); Very rare (popmax 0.00251%, amr); Associated with renal tubular dysgenesis of genetic origin.

What condition is associated with ACE p.Ile75Val (c.223A>G)?

ACE p.Ile75Val (c.223A>G) is associated with renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3, hemorrhage, intracerebral, susceptibility to (ClinVar).

How common is ACE p.Ile75Val (c.223A>G) in the general population?

ACE p.Ile75Val (c.223A>G) is very rare (popmax 0.00251%, amr) (gnomAD).

What do computational predictors say about ACE p.Ile75Val (c.223A>G)?

AlphaMissense predicts likely benign (score 0.1701) — an in-silico prediction, not a clinical call.

ACE p.Ile75Val

c.223A>G · VCV3582419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00251%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal tubular dysgenesis of genetic origin

Computational evidence

Protein change
AlphaMissense	0.1701	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00251% Admixed American · 1/39,792 alleles

Overall 0.000146% 2/1,369,214 alleles · very rare exomes 2/1,221,470 · genomes 0/147,744 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00251%	39,792
European (non-Finnish)	9.54e-05%	1,048,413

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.Ile75Val
Coding: c.223A>G
MANE Select: NM_000789
Type: single nucleotide variant
Location: chr17:63477317 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 75: the peptidase m2 1 domain

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

Disease context

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

Also linked: microvascular complications of diabetes, susceptibility to, 3 hemorrhage, intracerebral, susceptibility to

Similar variants

ACE c.1342+1G>T 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.Arg508Ter Pathogenic ★★ same condition
ACE p.Arg791Ter Pathogenic ★★ same condition
ACE p.Gln396Ter Pathogenic/Likely pathogenic ★★ same condition
ACE p.Met1Thr 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-ile75val (accessed [today's date]).

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