Is ACE p.Val423Met (c.1267G>A) pathogenic?

ACE p.Val423Met (c.1267G>A) is classified Uncertain significance in ACE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-13). AlphaMissense: likely benign (0.2315); Ultra-rare (popmax 0.025%, amr); Associated with microvascular complications of diabetes, susceptibility to, 3.

What condition is associated with ACE p.Val423Met (c.1267G>A)?

ACE p.Val423Met (c.1267G>A) is associated with microvascular complications of diabetes, susceptibility to, 3, renal tubular dysgenesis of genetic origin, hemorrhage, intracerebral, susceptibility to (ClinVar).

How common is ACE p.Val423Met (c.1267G>A) in the general population?

ACE p.Val423Met (c.1267G>A) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ACE p.Val423Met (c.1267G>A)?

AlphaMissense predicts likely benign (score 0.2315) — an in-silico prediction, not a clinical call.

ACE p.Val423Met

c.1267G>A · rs148018765 · VCV2190625

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

microvascular complications of diabetes, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.2315	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -10.62	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.72, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	26.8	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 0.025% Admixed American · 15/60,004 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00273% 44/1,613,990 alleles · ultra-rare exomes 38/1,461,802 · genomes 6/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,000
South Asian	0.011%	9,109
African / African-American	0.00934%	10,703
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.000763%	131,113

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.Val423Met
Coding: c.1267G>A
MANE Select: NM_000789
dbSNP: rs148018765
Type: single nucleotide variant
Location: chr17:63482614 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 423: an α-helix; the peptidase m2 1 domain

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

Disease context

microvascular complications of diabetes, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal tubular dysgenesis of genetic origin hemorrhage, intracerebral, susceptibility to

Similar variants

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
ACE p.Gln396Ter Pathogenic/Likely pathogenic ★★ same condition
ACE p.Met1Thr Pathogenic/Likely 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-val423met (accessed [today's date]).

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