# NM_000789.4(ACE):c.12_31del (p.Ser5fs)

https://sugi.bio/variant/ace-p-ser5fs

## Summary

**ACE p.Ser5fs (c.12_31del)** is classified **Pathogenic/Likely pathogenic** in ACE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-28). Ultra-rare (popmax 0.0288%, mid); Associated with renal tubular dysgenesis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs797045079 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0288%, mid)

## For patients & families {#patients}

This is a change in the ACE gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to renal tubular dysgenesis.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000379/index) · [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.Ser5fs |
| Coding change (HGVS c.) | c.12_31del |
| MANE Select transcript | [NM_000789](https://www.ncbi.nlm.nih.gov/nuccore/NM_000789) |
| dbSNP | [rs797045079](https://www.ncbi.nlm.nih.gov/snp/rs797045079/) |
| Variant type | Deletion |
| Location | chr17:63477106-63477125 (GRCh38) |
| ClinVar | [VCV208559](https://www.ncbi.nlm.nih.gov/clinvar/variation/208559/) |

**All HGVS expressions:** `NC_000017.10:g.61554467_61554486del`, `NC_000017.11:g.63477106_63477125del`, `NG_011648.1:g.5034_5053del`, `NM_000789.4:c.12_31del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.231, GERP 0.717, phastCons 0.142 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.88, pLI 6.2381e-32. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 25**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 22.9**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((GCTGCC)n). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.0288%** (mid) · FAF95 7.7e-05% · FAF99 2.1e-05% · 1/3,472 in the highest group · 4/1,317,378 alleles overall — ultra-rare (popmax 0.0288%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0288% | 3,472 |
| European (non-Finnish) | 0.000288% | 347,039 |

*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}


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.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-02-28.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2014–2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2014-09-24 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-02-28 |

## Associated conditions {#conditions}

[renal tubular dysgenesis](https://sugi.bio/atlas/disease/renal-tubular-dysgenesis/).

**Reported phenotype names (ClinVar):** Renal tubular dysgenesis, not provided, Renotubular dysgenesis, none provided.

## Similar variants {#similar}

Related ACE variant pages (same residue, condition, or type): [ACE p.Leu454fs](/variant/ace-p-leu454fs), [ACE p.Phe300fs](/variant/ace-p-phe300fs), [ACE p.Leu16_Pro23del](/variant/ace-p-leu16-pro23del), [ACE p.Ser5Leu](/variant/ace-p-ser5leu), [ACE p.Ser5=](/variant/ace-p-ser5), [ACE p.Leu440fs](/variant/ace-p-leu440fs), [ACE c.1709+5G>C](/variant/ace-c-1709-plus-5g-c), [ACE c.3503+1G>C](/variant/ace-c-3503-plus-1g-c).

### 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 208559). 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.*