# NM_001041.4(SI):c.545dup (p.Pro183fs)

https://sugi.bio/variant/si-p-pro183fs

## Summary

**SI p.Pro183fs (c.545dup)** is classified **Likely pathogenic** in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). Associated with congenital sucrase-isomaltase deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the SI gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to congenital sucrase-isomaltase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SI is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Congenital sucrase-isomaltase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Diarrhea — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Vomiting — Frequent (79-30%)
- Nausea — Frequent (79-30%)
- Constipation — Frequent (79-30%)
- Gastroesophageal reflux — Frequent (79-30%)
- Poor appetite — Frequent (79-30%)
- Flatulence — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006183/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SI](https://sugi.bio/atlas/gene/SI/) |
| Protein change (HGVS p.) | p.Pro183fs |
| Coding change (HGVS c.) | c.545dup |
| MANE Select transcript | [NM_001041](https://www.ncbi.nlm.nih.gov/nuccore/NM_001041) |
| Variant type | Duplication |
| Location | chr3:165067429-165067430 (GRCh38) |
| ClinVar | [VCV3588895](https://www.ncbi.nlm.nih.gov/clinvar/variation/3588895/) |

**All HGVS expressions:** `NC_000003.11:g.164785219dup`, `NC_000003.12:g.165067431dup`, `NG_017043.1:g.16066dup`, `NM_001041.4:c.545dup`

## 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 -0.535, GERP -3.49 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.009, pLI 7.6861e-32. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 48**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**SI** population constraint: LOEUF 1.009, pLI 7.6861e-32, missense-Z -0.89739; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **183** lies in the 'isomaltase' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.86, 86% of residues very-high.

**2 experimental structure(s)** (PDB): [3LPO](https://www.rcsb.org/structure/3LPO), [3LPP](https://www.rcsb.org/structure/3LPP).

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

*Describes the biological roles of SI (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:** SI's established molecular role includes oligo-1,6-glucosidase activity. p.Pro183fs falls in the isomaltase region. In Reactome, SI is annotated in disease pathway(s) including **Intestinal saccharidase deficiencies**.

**Disease mechanism (Reactome):** SI loss or alteration is curated in [Intestinal saccharidase deficiencies](https://reactome.org/content/detail/R-HSA-5659898).

### Pathways affected {#pathways}

SI participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Intestinal saccharidase deficiencies](https://reactome.org/content/detail/R-HSA-5659898) | electronic |
| [Digestion of dietary carbohydrate](https://reactome.org/content/detail/R-HSA-189085) | curated |

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

**Molecular function:** oligo-1,6-glucosidase activity, sucrose alpha-glucosidase activity.

**Biological process:** sucrose catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-06.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-06 |

## Associated conditions {#conditions}

[congenital sucrase-isomaltase deficiency](https://sugi.bio/atlas/disease/congenital-sucrase-isomaltase-deficiency/).

**Reported phenotype names (ClinVar):** Sucrase-isomaltase deficiency, SI DEFICIENCY, Deficiency of isomaltase, Congenital sucrose isomaltose malabsorption, Sucrose isomaltose enzyme deficiency.

## Similar variants {#similar}

Related SI variant pages (same residue, condition, or type): [SI p.Gln677fs](/variant/si-p-gln677fs), [SI p.His1210fs](/variant/si-p-his1210fs), [SI p.Phe1366fs](/variant/si-p-phe1366fs), [SI c.119-11dup](/variant/si-c-119-minus-11dup), [SI c.2737-23dup](/variant/si-c-2737-minus-23dup), [SI c.374-11dup](/variant/si-c-374-minus-11dup), [SI c.5198-20dup](/variant/si-c-5198-minus-20dup), [SI p.Asn1535fs](/variant/si-p-asn1535fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3588895). 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.*