Is ACE p.Arg561Trp (c.1681C>T) pathogenic?

ACE p.Arg561Trp (c.1681C>T) is classified Benign/Likely benign in ACE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1512); Rare (popmax 0.978%, afr); Associated with hemorrhage, intracerebral, susceptibility to.

What condition is associated with ACE p.Arg561Trp (c.1681C>T)?

ACE p.Arg561Trp (c.1681C>T) is associated with hemorrhage, intracerebral, susceptibility to, renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3 (ClinVar).

How common is ACE p.Arg561Trp (c.1681C>T) in the general population?

ACE p.Arg561Trp (c.1681C>T) is rare (popmax 0.978%, afr) (gnomAD).

What do computational predictors say about ACE p.Arg561Trp (c.1681C>T)?

AlphaMissense predicts likely benign (score 0.1512) — an in-silico prediction, not a clinical call.

ACE p.Arg561Trp

c.1681C>T · rs4314 · VCV890532

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1512 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.978%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemorrhage, intracerebral, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1512	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -12.23	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.19	GERP -2, phastCons 0.4
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	25.4	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 0.978% African / African-American · 734/75,024 alleles

Filtering AF 0.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.896%

Overall 0.0568% 917/1,614,008 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.978%	102
Admixed American	0.075%	1,334
Remaining individualsnot grpmax-eligible	0.0608%	1,645
Finnishnot grpmax-eligible	0.0235%	4,264
European (non-Finnish)	0.00703%	14,217
East Asian	0.00223%	44,866
South Asian	0.0011%	91,066

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.Arg561Trp
Coding: c.1681C>T
MANE Select: NM_000789
dbSNP: rs4314
Type: single nucleotide variant
Location: chr17:63483943 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 561: the peptidase m2 1 domain; a UniProt-annotated variant site (in)

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

Disease context

hemorrhage, intracerebral, susceptibility to — 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 renal tubular dysgenesis

Similar variants

ACE p.Arg561= Uncertain significance ★ 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.Arg508Ter 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-arg561trp (accessed [today's date]).

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