# NM_000789.4(ACE):c.3387T>C (p.Phe1129=)

https://sugi.bio/variant/ace-p-phe1129

## Summary

**ACE p.Phe1129= (c.3387T>C)** is classified **Benign/Likely benign** in ACE (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 61.3%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hemorrhage, intracerebral, susceptibility to.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs4362 · 9 submitters · 4 linked conditions · common (popmax 61.3%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ACE gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters, and is linked to hemorrhage, intracerebral, susceptibility to.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACE](https://sugi.bio/atlas/gene/ACE/) |
| Protein change (HGVS p.) | p.Phe1129= |
| Coding change (HGVS c.) | c.3387T>C |
| MANE Select transcript | [NM_000789](https://www.ncbi.nlm.nih.gov/nuccore/NM_000789) |
| dbSNP | [rs4362](https://www.ncbi.nlm.nih.gov/snp/rs4362/) |
| Variant type | single nucleotide variant |
| Location | chr17:63496400-63496400 (GRCh38) |
| ClinVar | [VCV256804](https://www.ncbi.nlm.nih.gov/clinvar/variation/256804/) |

**All HGVS expressions:** `NC_000017.10:g.61573761T>C`, `NC_000017.11:g.63496400T>C`, `NG_011648.1:g.24328T>C`, `NM_000789.4:c.3387T>C`, `NM_001178057.2:c.1659-398T>C`, `NM_152830.3:c.1665T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 61.3%, sas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -8.259, GERP -3.67 — fast-evolving / accelerated position
- CADD: **PHRED 0.46**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.61 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **61.3%** (sas) · FAF95 60.9% · FAF99 60.7% · 55,850/91,062 in the highest group · 800,917/1,613,968 alleles overall — common (popmax 61.3%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 61.3% | 2 |
| East Asian | 58.6% | 2 |
| Admixed American | 58.3% | 2 |
| African / African-American | 57.6% | 2 |
| Remaining individuals (not grpmax-eligible) | 49.7% | 2 |
| European (non-Finnish) | 48% | 2 |
| Finnish (not grpmax-eligible) | 45.8% | 2 |
| Amish (not grpmax-eligible) | 41.5% | 2 |
| Middle Eastern | 41.1% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 37.3% | 3 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ACE** population constraint: LOEUF 0.88, pLI 6.2381e-32, missense-Z -0.50314. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **renal tubular dysgenesis - ACE** — Definitive (AR)

## Protein context {#protein}

Residue **1129** lies in an α-helix; the peptidase m2 2 domain.

AlphaFold model confidence (whole protein): pLDDT 91.38, 82% of residues very-high.

**97 experimental structure(s)** (PDB): [1O86](https://www.rcsb.org/structure/1O86), [1O8A](https://www.rcsb.org/structure/1O8A), [1UZE](https://www.rcsb.org/structure/1UZE), [1UZF](https://www.rcsb.org/structure/1UZF), [2C6F](https://www.rcsb.org/structure/2C6F), [2C6N](https://www.rcsb.org/structure/2C6N) — incl. mutant structure 2IUL.

## What this gene does {#gene-function}

*Describes the biological roles of ACE (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ACE's established molecular role includes actin binding. p.Phe1129= falls in the peptidase m2 2 domain.


### Pathways affected {#pathways}

ACE participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Metabolism of Angiotensinogen to Angiotensins](https://reactome.org/content/detail/R-HSA-2022377) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** actin binding, endopeptidase activity, metalloendopeptidase activity, peptidase activity, metallopeptidase activity, exopeptidase activity.

**Biological process:** kidney development, angiotensin maturation, regulation of systemic arterial blood pressure by renin-angiotensin, substance P catabolic process, bradykinin catabolic process, hormone metabolic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (8 Benign, 1 Likely benign).

**Submission history:** 9 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-11-10 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-11 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-03-09 |

## Associated conditions {#conditions}

[hemorrhage, intracerebral, susceptibility to](https://sugi.bio/atlas/disease/hemorrhage-intracerebral-susceptibility-to/), [renal tubular dysgenesis of genetic origin](https://sugi.bio/atlas/disease/renal-tubular-dysgenesis-of-genetic-origin/), [microvascular complications of diabetes, susceptibility to, 3](https://sugi.bio/atlas/disease/microvascular-complications-of-diabetes-susceptibility-to-3/), [renal tubular dysgenesis](https://sugi.bio/atlas/disease/renal-tubular-dysgenesis/).

**Reported phenotype names (ClinVar):** Hemorrhage, intracerebral, susceptibility to, not specified, Renal tubular dysgenesis, not provided, Microvascular complications of diabetes, susceptibility to, 3, Renal tubular dysgenesis of genetic origin, Stroke, hemorrhagic, susceptibility to, PRIMITIVE RENAL TUBULE SYNDROME, Renotubular dysgenesis, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACE variant pages (same residue, condition, or type): [ACE c.1342+1G>T](/variant/ace-c-1342-plus-1g-t), [ACE c.1709+5G>C](/variant/ace-c-1709-plus-5g-c), [ACE c.3503+1G>C](/variant/ace-c-3503-plus-1g-c), [ACE c.945+2T>G](/variant/ace-c-945-plus-2t-g), [ACE p.Arg265Ter](/variant/ace-p-arg265ter), [ACE p.Arg496Ter](/variant/ace-p-arg496ter), [ACE p.Arg508Ter](/variant/ace-p-arg508ter), [ACE p.Arg791Ter](/variant/ace-p-arg791ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 256804). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*