Is ACE p.Gln376Arg (c.1127A>G) pathogenic?

ACE p.Gln376Arg (c.1127A>G) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely pathogenic (0.8689); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ACE p.Gln376Arg (c.1127A>G)?

ACE p.Gln376Arg (c.1127A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACE p.Gln376Arg (c.1127A>G) in the general population?

ACE p.Gln376Arg (c.1127A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACE p.Gln376Arg (c.1127A>G)?

AlphaMissense predicts likely pathogenic (score 0.8689) — an in-silico prediction, not a clinical call.

ACE p.Gln376Arg

c.1127A>G · rs2510688410 · VCV2236246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8689 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8689	likely pathogenic
REVEL	0.632	indeterminate
SaProt	LLR -15.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACE
Protein: p.Gln376Arg
Coding: c.1127A>G
MANE Select: NM_000789
dbSNP: rs2510688410
Type: single nucleotide variant
Location: chr17:63482474 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 376: a disulfide bond; the peptidase m2 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACE p.Gln376Ter Likely pathogenic ★ same residue
ACE p.Ala225Ser Uncertain significance ★★ ⚠ same condition
ACE p.Ala361Thr Uncertain significance ★★ ⚠ same condition
ACE p.Arg814Gln Uncertain significance ★★ ⚠ same condition
ACE p.Asn671Ser Uncertain significance ★★ ⚠ same condition
ACE p.Asp746Asn Uncertain significance ★★ ⚠ same condition
ACE p.Gln25Leu Uncertain significance ★★ ⚠ same condition
ACE p.Glu638Lys 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-gln376arg (accessed [today's date]).

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