Is ACE p.Ala731Val (c.2192C>T) pathogenic?

ACE p.Ala731Val (c.2192C>T) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-06). AlphaMissense: likely benign (0.1128); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACE p.Ala731Val (c.2192C>T)?

ACE p.Ala731Val (c.2192C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACE p.Ala731Val (c.2192C>T) in the general population?

ACE p.Ala731Val (c.2192C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about ACE p.Ala731Val (c.2192C>T)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

ACE p.Ala731Val

c.2192C>T · rs1374995262 · VCV2471854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1128	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.46	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	GERP -0.59, phastCons 0.56
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	14.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.016% African / African-American · 12/74,940 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.0013% 21/1,614,110 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,245
East Asian	0.00445%	22,450
South Asian	0.0011%	91,092
European (non-Finnish)	0.000508%	196,676

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.Ala731Val
Coding: c.2192C>T
MANE Select: NM_000789
dbSNP: rs1374995262
Type: single nucleotide variant
Location: chr17:63486690 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 731: an α-helix; the peptidase m2 2 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.Ala731= Benign ★★ 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-ala731val (accessed [today's date]).

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