# NM_001080543.2(CACTIN):c.148C>T (p.Arg50Trp)

https://sugi.bio/variant/cactin-p-arg50trp

## Summary

**CACTIN p.Arg50Trp (c.148C>T)** is classified **Uncertain significance** in CACTIN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely benign (0.1185); Ultra-rare (popmax 0.0103%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0103%, nfe)

## For patients & families {#patients}

This is a change in the CACTIN 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 | [CACTIN](https://sugi.bio/atlas/gene/CACTIN/) |
| Protein change (HGVS p.) | p.Arg50Trp |
| Coding change (HGVS c.) | c.148C>T |
| MANE Select transcript | [NM_001080543](https://www.ncbi.nlm.nih.gov/nuccore/NM_001080543) |
| Variant type | single nucleotide variant |
| Location | chr19:3626615-3626615 (GRCh38) |
| ClinVar | [VCV3484226](https://www.ncbi.nlm.nih.gov/clinvar/variation/3484226/) |

**All HGVS expressions:** `NC_000019.10:g.3626615G>A`, `NC_000019.9:g.3626613G>A`, `NG_140015.1:g.413G>A`, `NG_140015.2:g.413G>A`, `NM_001080543.2:c.148C>T`, `NM_021231.2:c.148C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1185)
- REVEL 0.14 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.933 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.371, GERP -3.49, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.4**. 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 1.07** across the covering region of the MANE Select transcript (3,623,853–3,626,762), spanning 2,909 bp. Chi-square p 0.27. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.03**, acceptor gain **0.00**, donor gain **0.24**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.03**, acceptor gain **0.00**, donor gain **0.24**.
- Population frequency (gnomAD v4.1): grpmax **0.0103%** (nfe) · FAF95 0.00874% · FAF99 0.00817% · 117/1,137,086 in the highest group · 119/1,510,528 alleles overall — ultra-rare (popmax 0.0103%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0103% | 9,719 |
| Remaining individuals (not grpmax-eligible) | 0.00344% | 29,048 |

*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}

**CACTIN** population constraint: LOEUF 0.465, pLI 0.99735, missense-Z 1.3409. *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 **50** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 69.52, 13% of residues very-high.

**6 experimental structure(s)** (PDB): [6QDV](https://www.rcsb.org/structure/6QDV), [7W5A](https://www.rcsb.org/structure/7W5A), [7W5B](https://www.rcsb.org/structure/7W5B), [8C6J](https://www.rcsb.org/structure/8C6J), [9FMD](https://www.rcsb.org/structure/9FMD), [9XU3](https://www.rcsb.org/structure/9XU3).

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

*Describes the biological roles of CACTIN (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:** CACTIN's established molecular role includes RNA binding. p.Arg50Trp falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

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

**Molecular function:** RNA binding.

**Biological process:** mRNA splicing, via spliceosome, negative regulation of protein phosphorylation, negative regulation of lipopolysaccharide-mediated signaling pathway, negative regulation of interferon-beta production, negative regulation of interleukin-8 production, negative regulation of tumor necrosis factor production.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-28.

**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 | 2024-06-28 |

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

## Similar variants {#similar}

Related CACTIN variant pages (same residue, condition, or type): [CACTIN p.Ala100Ser](/variant/cactin-p-ala100ser), [CACTIN p.Ala119Val](/variant/cactin-p-ala119val), [CACTIN p.Ala130Ser](/variant/cactin-p-ala130ser), [CACTIN p.Ala131Val](/variant/cactin-p-ala131val), [CACTIN p.Ala317Thr](/variant/cactin-p-ala317thr), [CACTIN p.Ala427Thr](/variant/cactin-p-ala427thr), [CACTIN p.Ala500Val](/variant/cactin-p-ala500val), [CACTIN p.Arg102Gln](/variant/cactin-p-arg102gln).

### 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 3484226). 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.*