# NM_001099.5(ACP3):c.469C>T (p.Pro157Ser)

https://sugi.bio/variant/acp3-p-pro157ser

## Summary

**ACP3 p.Pro157Ser (c.469C>T)** is classified **Uncertain significance** in ACP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.731); Very rare (popmax 0.00446%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the ACP3 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 | [ACP3](https://sugi.bio/atlas/gene/ACP3/) |
| Protein change (HGVS p.) | p.Pro157Ser |
| Coding change (HGVS c.) | c.469C>T |
| MANE Select transcript | [NM_001099](https://www.ncbi.nlm.nih.gov/nuccore/NM_001099) |
| Variant type | single nucleotide variant |
| Location | chr3:132337468-132337468 (GRCh38) |
| ClinVar | [VCV3262477](https://www.ncbi.nlm.nih.gov/clinvar/variation/3262477/) |

**All HGVS expressions:** `NC_000003.11:g.132056312C>T`, `NC_000003.12:g.132337468C>T`, `NG_047032.1:g.25102C>T`, `NM_001099.5:c.469C>T`, `NM_001134194.2:c.469C>T`, `NM_001292037.2:c.457-5084C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.731)
- REVEL 0.234 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -7.157 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.803, GERP 1.85, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.5**. 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.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (132,317,457–132,356,875), spanning 39,418 bp. Chi-square p 0.9. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.11**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Pangolin: Δ**0.55** (gain), gain 0.55 / loss 0.40. 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 **0.00446%** (eas) · FAF95 0.00074% · FAF99 0.000277% · 2/44,796 in the highest group · 6/1,455,798 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00482% | 20,749 |
| East Asian (grpmax) | 0.00446% | 22,398 |
| South Asian | 0.0011% | 90,540 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ACP3** population constraint: LOEUF 1.079, pLI 4.4344e-07, missense-Z 0.3975. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.51, 87% of residues very-high.

**17 experimental structure(s)** (PDB): [1CVI](https://www.rcsb.org/structure/1CVI), [1ND5](https://www.rcsb.org/structure/1ND5), [1ND6](https://www.rcsb.org/structure/1ND6), [2HPA](https://www.rcsb.org/structure/2HPA), [2L3H](https://www.rcsb.org/structure/2L3H), [2L77](https://www.rcsb.org/structure/2L77) — incl. mutant structure 9NMX.

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

*Describes the biological roles of ACP3 (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:** ACP3's established molecular role includes acid phosphatase activity.


### Pathways affected {#pathways}

ACP3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** acid phosphatase activity, 5'-nucleotidase activity, phosphatase activity, identical protein binding, protein homodimerization activity, lysophosphatidic acid phosphatase activity.

**Biological process:** adenosine metabolic process, regulation of sensory perception of pain, positive regulation of adenosine receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-19 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACP3 variant pages (same residue, condition, or type): [ACP3 p.Asp301Glu](/variant/acp3-p-asp301glu), [ACP3 p.Ala116Ser](/variant/acp3-p-ala116ser), [ACP3 p.Ala121Ser](/variant/acp3-p-ala121ser), [ACP3 p.Ala311Thr](/variant/acp3-p-ala311thr), [ACP3 p.Ala4Thr](/variant/acp3-p-ala4thr), [ACP3 p.Ala9Thr](/variant/acp3-p-ala9thr), [ACP3 p.Arg111Gln](/variant/acp3-p-arg111gln), [ACP3 p.Arg111Trp](/variant/acp3-p-arg111trp).

### 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 3262477). 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.*