Is ACE p.Thr331Ala (c.991A>G) pathogenic?

ACE p.Thr331Ala (c.991A>G) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.0982); Very rare (popmax 0.00439%, sas).

How common is ACE p.Thr331Ala (c.991A>G) in the general population?

ACE p.Thr331Ala (c.991A>G) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ACE p.Thr331Ala (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

ACE p.Thr331Ala

c.991A>G · rs2510687476 · VCV2690829

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -11.26	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	21.1	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 0.00439% South Asian · 4/91,034 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00041% 6/1,461,736 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,759
East Asian	0.00223%	44,806
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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.Thr331Ala
Coding: c.991A>G
MANE Select: NM_000789
dbSNP: rs2510687476
Type: single nucleotide variant
Location: chr17:63481611 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 331: an α-helix; the peptidase m2 1 domain

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

Similar variants

ACE p.Thr331= Likely benign ★ 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-thr331ala (accessed [today's date]).

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