# NM_018367.7(ACER3):c.424_426delinsTCA (p.Pro142Ser)

https://sugi.bio/variant/acer3-p-pro142ser

## Summary

**ACER3 p.Pro142Ser (c.424_426delinsTCA)** is classified **Uncertain significance** in ACER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the ACER3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACER3](https://sugi.bio/atlas/gene/ACER3/) |
| Protein change (HGVS p.) | p.Pro142Ser |
| Coding change (HGVS c.) | c.424_426delinsTCA |
| MANE Select transcript | [NM_018367](https://www.ncbi.nlm.nih.gov/nuccore/NM_018367) |
| Variant type | Indel |
| Location | chr11:76990560-76990562 (GRCh38) |
| ClinVar | [VCV4083425](https://www.ncbi.nlm.nih.gov/clinvar/variation/4083425/) |

**All HGVS expressions:** `NC_000011.10:g.76990560_76990562delinsTCA`, `NC_000011.9:g.76701604_76701606delinsTCA`, `NM_001300953.2:c.313_315delinsTCA`, `NM_001300954.2:c.139_141delinsTCA`, `NM_001300955.2:c.139_141delinsTCA`, `NM_018367.7:c.424_426delinsTCA`

## 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 7.528, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.67** across the covering region of the MANE Select transcript (76,861,017–77,020,277), spanning 159,260 bp. Chi-square p 1.9e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**ACER3** population constraint: LOEUF 0.815, pLI 0.30464, missense-Z 0.87127. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **142** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.23, 86% of residues very-high.

**2 experimental structure(s)** (PDB): [6G7O](https://www.rcsb.org/structure/6G7O), [6YXH](https://www.rcsb.org/structure/6YXH).

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

*Describes the biological roles of ACER3 (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:** ACER3's established molecular role includes calcium ion binding.


### Pathways affected {#pathways}

ACER3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9845614) | curated |

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

**Molecular function:** calcium ion binding, zinc ion binding, N-acylsphingosine amidohydrolase activity.

**Biological process:** positive regulation of cell population proliferation, myelination, regulation of programmed cell death, sphingosine biosynthetic process, ceramide catabolic process, phytosphingosine biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-14 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ACER3 variant pages (same residue, condition, or type): [ACER3 p.Pro142=](/variant/acer3-p-pro142), [ACER3 p.Arg62Trp](/variant/acer3-p-arg62trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4083425). 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.*