Is ACE p.Arg508Gln (c.1523G>A) pathogenic?

ACE p.Arg508Gln (c.1523G>A) is classified Uncertain significance in ACE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.5838); Very rare (popmax 0.00466%, nfe); Associated with renal tubular dysgenesis.

What condition is associated with ACE p.Arg508Gln (c.1523G>A)?

ACE p.Arg508Gln (c.1523G>A) is associated with renal tubular dysgenesis, renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3 (ClinVar).

How common is ACE p.Arg508Gln (c.1523G>A) in the general population?

ACE p.Arg508Gln (c.1523G>A) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about ACE p.Arg508Gln (c.1523G>A)?

AlphaMissense predicts likely pathogenic (score 0.5838) — an in-silico prediction, not a clinical call.

ACE p.Arg508Gln

c.1523G>A · rs746397573 · VCV324382

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal tubular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.5838	likely pathogenic
REVEL	0.5	indeterminate
SaProt	LLR -13.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.25	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00466% European (non-Finnish) · 55/1,180,022 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00384% 62/1,613,976 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00466%	21,455
East Asian	0.00446%	22,446
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed American	0.00167%	59,992
African / African-American	0.00134%	74,880
South Asian	0.0011%	91,082

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.Arg508Gln
Coding: c.1523G>A
MANE Select: NM_000789
dbSNP: rs746397573
Type: single nucleotide variant
Location: chr17:63483495 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 508: 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 p.Arg508Ter Pathogenic ★★ 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
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-arg508gln (accessed [today's date]).

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