# NM_006929.5(SKIC2):c.132C>T (p.Pro44=)

https://sugi.bio/variant/skic2-p-pro44

## Summary

**SKIC2 p.Pro44= (c.132C>T)** is classified **Conflicting classifications of pathogenicity** in SKIC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-26). Absent from gnomAD v4.1; Associated with trichohepatoenteric syndrome 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs886061306 · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SKIC2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to trichohepatoenteric syndrome 2.

*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) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | SKIC2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Trichohepatoenteric syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal facial shape — Very frequent (99-80%)
- Intractable diarrhea — Very frequent (99-80%)
- Woolly hair — Very frequent (99-80%)
- Immunodeficiency — Very frequent (99-80%)
- Hypertelorism — Frequent (79-30%)
- Broad forehead — Frequent (79-30%)
- Wide nasal bridge — Frequent (79-30%)
- Intellectual disability, mild — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015819/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SKIC2](https://sugi.bio/atlas/gene/SKIC2/) |
| Protein change (HGVS p.) | p.Pro44= |
| Coding change (HGVS c.) | c.132C>T |
| MANE Select transcript | [NM_006929](https://www.ncbi.nlm.nih.gov/nuccore/NM_006929) |
| dbSNP | [rs886061306](https://www.ncbi.nlm.nih.gov/snp/rs886061306/) |
| Variant type | single nucleotide variant |
| Location | chr6:31960015-31960015 (GRCh38) |
| ClinVar | [VCV356311](https://www.ncbi.nlm.nih.gov/clinvar/variation/356311/) |

**All HGVS expressions:** `NC_000006.11:g.31927792C>T`, `NC_000006.12:g.31960015C>T`, `NG_032652.1:g.6212C>T`, `NM_006929.5:c.132C>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 **acceptor gain** (Δ 0.35) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.028, GERP -0.856, phastCons 0.813 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.9**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


Curated gene–disease validity (ClinGen):

- **trichohepatoenteric syndrome 2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.32, 41% of residues very-high.

**11 experimental structure(s)** (PDB): [7QDR](https://www.rcsb.org/structure/7QDR), [7QDS](https://www.rcsb.org/structure/7QDS), [7QDY](https://www.rcsb.org/structure/7QDY), [7QDZ](https://www.rcsb.org/structure/7QDZ), [7QE0](https://www.rcsb.org/structure/7QE0), [9G8M](https://www.rcsb.org/structure/9G8M).

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

*Describes the biological roles of SKIC2 (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:** SKIC2's established molecular role includes 3'-5' RNA helicase activity.


### Pathways affected {#pathways}

SKIC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [mRNA decay by 3' to 5' exoribonuclease](https://reactome.org/content/detail/R-HSA-429958) | curated |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | electronic |

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

**Molecular function:** 3'-5' RNA helicase activity.

**Biological process:** nuclear-transcribed mRNA catabolic process, nuclear-transcribed mRNA catabolic process, 3'-5' exonucleolytic nonsense-mediated decay, nuclear-transcribed mRNA catabolic process, non-stop decay, rescue of stalled cytosolic ribosome.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-26.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-26 |

## Associated conditions {#conditions}

[trichohepatoenteric syndrome 2](https://sugi.bio/atlas/disease/trichohepatoenteric-syndrome-2/).

**Reported phenotype names (ClinVar):** Trichohepatoenteric syndrome 2, not provided, none provided.

## Similar variants {#similar}

Related SKIC2 variant pages (same residue, condition, or type): [SKIC2 p.Pro44Ser](/variant/skic2-p-pro44ser), [SKIC2 c.1404-2A>G](/variant/skic2-c-1404-minus-2a-g), [SKIC2 c.2203-1G>A](/variant/skic2-c-2203-minus-1g-a), [SKIC2 c.2341-1G>T](/variant/skic2-c-2341-minus-1g-t), [SKIC2 c.2341-2A>G](/variant/skic2-c-2341-minus-2a-g), [SKIC2 c.470-1G>A](/variant/skic2-c-470-minus-1g-a), [SKIC2 p.Arg1063Ter](/variant/skic2-p-arg1063ter), [SKIC2 p.Arg253Ter](/variant/skic2-p-arg253ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 356311). 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.*