Is ACE p.Arg8fs (c.21_30del) pathogenic?

ACE p.Arg8fs (c.2130del) is classified Pathogenic/Likely pathogenic in ACE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-27). Very rare (popmax 0.00415%, amr); Associated with hemorrhage, intracerebral, susceptibility to.

What condition is associated with ACE p.Arg8fs (c.21_30del)?

ACE p.Arg8fs (c.21_30del) 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.Arg8fs (c.21_30del) in the general population?

ACE p.Arg8fs (c.21_30del) is very rare (popmax 0.00415%, amr) (gnomAD).

ACE p.Arg8fs

c.21_30del · VCV3341107

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00415%, amr)

Conditions

hemorrhage, intracerebral, susceptibility to

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.3	GERP -0.4
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(GCTGCC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% Admixed American · 1/24,110 alleles

Filtering AF 0.000207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000606% 8/1,320,906 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00415%	24,110
African / African-American	0.00156%	64,138
European (non-Finnish)	0.000575%	173,856

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.Arg8fs
Coding: c.21_30del
MANE Select: NM_000789
Type: Deletion
Location: chr17:63477109 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB

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

Similar variants

ACE p.Arg8Trp Uncertain significance ★★ ⚠ same residue
ACE p.Arg8Leu Uncertain significance ★ ⚠ same residue
ACE p.Pro504fs Likely pathogenic ★★ same condition
ACE p.Arg862fs Likely pathogenic ★ same condition
ACE p.Lys722fs Likely pathogenic ★ same condition
ACE p.Ser1131fs Likely pathogenic ★ same condition
ACE p.Val325fs Likely pathogenic ★ same condition
ACE c.1922-236_1922-219del 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-arg8fs (accessed [today's date]).

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