# NM_001041.4(SI):c.876C>T (p.Phe292=)

https://sugi.bio/variant/si-p-phe292

## Summary

**SI p.Phe292= (c.876C>T)** is classified **Likely benign** in SI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). Rare (popmax 0.186%, afr); Associated with congenital sucrase-isomaltase deficiency.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs139642816 · 4 submitters · 1 linked condition · rare (popmax 0.186%, afr)

## For patients & families {#patients}

This is a change in the SI gene that is classified as likely benign — not considered disease-causing, submitted by 4 submitters, 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.Phe292= |
| Coding change (HGVS c.) | c.876C>T |
| MANE Select transcript | [NM_001041](https://www.ncbi.nlm.nih.gov/nuccore/NM_001041) |
| dbSNP | [rs139642816](https://www.ncbi.nlm.nih.gov/snp/rs139642816/) |
| Variant type | single nucleotide variant |
| Location | chr3:165063473-165063473 (GRCh38) |
| ClinVar | [VCV1621810](https://www.ncbi.nlm.nih.gov/clinvar/variation/1621810/) |

**All HGVS expressions:** `NC_000003.11:g.164781261G>A`, `NC_000003.12:g.165063473G>A`, `NG_017043.1:g.20023C>T`, `NM_001041.3:c.876C>T`, `NM_001041.4:c.876C>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 (below), not from a missing predictor score.
- Conservation: phyloP 2.668, GERP -2.58, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.267**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.37 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.186%** (afr) · FAF95 0.16% · FAF99 0.151% · 136/73,184 in the highest group · 192/1,546,678 alleles overall — rare (popmax 0.186%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.186% | 538 |
| Remaining individuals (not grpmax-eligible) | 0.0233% | 4,285 |
| Middle Eastern | 0.0169% | 5,910 |
| Admixed American | 0.0169% | 5,914 |
| East Asian | 0.00457% | 21,887 |
| South Asian | 0.00341% | 29,306 |
| European (non-Finnish) | 0.00231% | 43,221 |

*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 30, triplosensitivity Not yet evaluated (0–3 scale). *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 **292** lies in the 'isomaltase' region; a β-strand.

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.Phe292= 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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-21.

**Submitter consensus:** unanimous (4/4 Likely benign).

**Submission history:** 4 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-19 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-12-08 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Sucrase-isomaltase deficiency, SI-related disorder, not provided, none provided, SI-related condition, Congenital sucrose isomaltose malabsorption, Sucrose isomaltose enzyme deficiency, Deficiency of isomaltase, SI DEFICIENCY.

## Similar variants {#similar}

Related SI variant pages (same residue, condition, or type): [SI p.Phe292Leu](/variant/si-p-phe292leu), [SI c.2426+1G>A](/variant/si-c-2426-plus-1g-a), [SI c.2893-1G>A](/variant/si-c-2893-minus-1g-a), [SI c.3099+1G>C](/variant/si-c-3099-plus-1g-c), [SI c.3521-1G>T](/variant/si-c-3521-minus-1g-t), [SI c.373+1G>A](/variant/si-c-373-plus-1g-a), [SI c.4575+2T>C](/variant/si-c-4575-plus-2t-c), [SI c.4927-1G>A](/variant/si-c-4927-minus-1g-a).

### 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 1621810). 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.*