Is ACE p.Pro1180Leu (c.3539C>T) pathogenic?

ACE p.Pro1180Leu (c.3539C>T) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.2671); Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACE p.Pro1180Leu (c.3539C>T)?

ACE p.Pro1180Leu (c.3539C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACE p.Pro1180Leu (c.3539C>T) in the general population?

ACE p.Pro1180Leu (c.3539C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about ACE p.Pro1180Leu (c.3539C>T)?

AlphaMissense predicts likely benign (score 0.2671) — an in-silico prediction, not a clinical call.

ACE p.Pro1180Leu

c.3539C>T · rs775501006 · VCV2277838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2671	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -11.42	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	23.8	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 0.02% Admixed American · 12/60,008 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00279% 45/1,612,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
Remaining individualsnot grpmax-eligible	0.0096%	10,412
European (non-Finnish)	0.00229%	43,705

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.Pro1180Leu
Coding: c.3539C>T
MANE Select: NM_000789
dbSNP: rs775501006
Type: single nucleotide variant
Location: chr17:63496833 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 1180: 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.Pro1180= Likely 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-pro1180leu (accessed [today's date]).

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