Is ACE p.Arg442His (c.1325G>A) pathogenic?

ACE p.Arg442His (c.1325G>A) is classified Benign/Likely benign in ACE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.0547); Low-frequency (popmax 1.44%, afr).

How common is ACE p.Arg442His (c.1325G>A) in the general population?

ACE p.Arg442His (c.1325G>A) is low-frequency (popmax 1.44%, afr) (gnomAD).

What do computational predictors say about ACE p.Arg442His (c.1325G>A)?

AlphaMissense predicts likely benign (score 0.0547) — an in-silico prediction, not a clinical call.

ACE p.Arg442His

c.1325G>A · rs35865660 · VCV789095

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0547 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.44%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0547	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -7.87	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 -1.2	GERP -3.7
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	1.267	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 1.44% African / African-American · 1,078/75,038 alleles

Filtering AF 1.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.34%

Overall 0.0881% 1,422/1,613,814 alleles · low-frequency exomes 752/1,461,508 · genomes 670/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.44%	70
Admixed American	0.142%	706
Remaining individualsnot grpmax-eligible	0.134%	744
Middle Eastern	0.033%	3,030
South Asian	0.0263%	3,795
European (non-Finnish)	0.0123%	8,138
East Asian	0.00891%	11,219

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.Arg442His
Coding: c.1325G>A
MANE Select: NM_000789
dbSNP: rs35865660
Type: single nucleotide variant
Location: chr17:63482672 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 442: an α-helix; a binding site; the peptidase m2 1 domain

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

Similar variants

ACE p.Arg442Cys Uncertain significance ★ ⚠ same residue
ACE c.1342+1G>T Likely pathogenic ★★ same type
ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same type
ACE c.3503+1G>C Likely pathogenic ★★ same type
ACE c.945+2T>G Likely pathogenic ★★ same type
ACE p.Arg265Ter Pathogenic ★★ same type
ACE p.Arg496Gln Likely pathogenic ★★ same type
ACE p.Arg496Ter Pathogenic/Likely pathogenic ★★ same type

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-arg442his (accessed [today's date]).

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