# NM_000789.4(ACE):c.2049C>T (p.Ser683=)

https://sugi.bio/variant/ace-p-ser683

## Summary

**ACE p.Ser683= (c.2049C>T)** is classified **Uncertain significance** in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-09). Very rare (popmax 0.00644%, nfe); Associated with renal tubular dysgenesis of genetic origin.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 3 linked conditions · very rare (popmax 0.00644%, nfe)

## For patients & families {#patients}

This is a change in the ACE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to renal tubular dysgenesis of genetic origin.

*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/0016854/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.Ser683= |
| Coding change (HGVS c.) | c.2049C>T |
| MANE Select transcript | [NM_000789](https://www.ncbi.nlm.nih.gov/nuccore/NM_000789) |
| Variant type | single nucleotide variant |
| Location | chr17:63485363-63485363 (GRCh38) |
| ClinVar | [VCV3582514](https://www.ncbi.nlm.nih.gov/clinvar/variation/3582514/) |

**All HGVS expressions:** `NC_000017.10:g.61562724C>T`, `NC_000017.11:g.63485363C>T`, `NG_011648.1:g.13291C>T`, `NM_000789.4:c.2049C>T`, `NM_001178057.2:c.327C>T`, `NM_001382700.1:c.1482C>T`, `NM_001382701.1:c.1197C>T`, `NM_001382702.1:c.-22C>T`, `NM_152830.3:c.327C>T`, `NR_168483.1:n.349C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.98) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.33, GERP 0.414, phastCons 0.998 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.99**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.63**, acceptor gain **0.00**, donor gain **0.98**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.63**, acceptor gain **0.00**, donor gain **0.98**.
- Pangolin: Δ**0.84** (gain), gain 0.84 / loss 0.63. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00644%** (nfe) · FAF95 0.00528% · FAF99 0.00482% · 76/1,180,014 in the highest group · 77/1,613,960 alleles overall — very rare (popmax 0.00644%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00644% | 15,527 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |

*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 **683** 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.Ser683= 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-09 |

## Associated conditions {#conditions}

[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/), [hemorrhage, intracerebral, susceptibility to](https://sugi.bio/atlas/disease/hemorrhage-intracerebral-susceptibility-to/).

**Reported phenotype names (ClinVar):** Renal tubular dysgenesis of genetic origin, Hemorrhage, intracerebral, susceptibility to, Microvascular complications of diabetes, susceptibility to, 3, PRIMITIVE RENAL TUBULE SYNDROME, Stroke, hemorrhagic, susceptibility to.

## Similar variants {#similar}

Related ACE variant pages (same residue, condition, or type): [ACE p.Ser683Arg](/variant/ace-p-ser683arg), [ACE c.1342+1G>T](/variant/ace-c-1342-plus-1g-t), [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.Arg508Ter](/variant/ace-p-arg508ter), [ACE p.Arg791Ter](/variant/ace-p-arg791ter), [ACE p.Gln396Ter](/variant/ace-p-gln396ter).

### 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 3582514). 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.*