Is ACE p.Arg137Trp (c.409C>T) pathogenic?

ACE p.Arg137Trp (c.409C>T) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: ambiguous (0.5314); Very rare (popmax 8.58e-05%, nfe); Associated with renal tubular dysgenesis of genetic origin.

What condition is associated with ACE p.Arg137Trp (c.409C>T)?

ACE p.Arg137Trp (c.409C>T) 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.Arg137Trp (c.409C>T) in the general population?

ACE p.Arg137Trp (c.409C>T) is very rare (popmax 8.58e-05%, nfe) (gnomAD).

What do computational predictors say about ACE p.Arg137Trp (c.409C>T)?

AlphaMissense predicts ambiguous (score 0.5314) — an in-silico prediction, not a clinical call.

ACE p.Arg137Trp

c.409C>T · VCV3582430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5314 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.58e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

renal tubular dysgenesis of genetic origin

Computational evidence

Protein change
AlphaMissense	0.5314	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -12.04	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.98	GERP 0.71, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	25.8	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 8.58e-05% European (non-Finnish) · 1/1,165,276 alleles

Overall 6.31e-05% 1/1,584,334 alleles · very rare exomes 1/1,431,976 · genomes 0/152,358 · joint denominator

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.Arg137Trp
Coding: c.409C>T
MANE Select: NM_000789
Type: single nucleotide variant
Location: chr17:63478090 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 137: 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 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 p.Arg137Gln Uncertain significance ★ ⚠ same residue
ACE p.Arg137= Conflicting classifications of pathogenicity ★ same residue
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

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-arg137trp (accessed [today's date]).

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