# NM_003380.5(VIM):c.23C>T (p.Ser8Leu)

https://sugi.bio/variant/vim-p-ser8leu

## Summary

**VIM p.Ser8Leu (c.23C>T)** is classified **Uncertain significance** in VIM (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-01). AlphaMissense: likely benign (0.211); Very rare (popmax 0.000254%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs779204525 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the VIM 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 | [VIM](https://sugi.bio/atlas/gene/VIM/) |
| Protein change (HGVS p.) | p.Ser8Leu |
| Coding change (HGVS c.) | c.23C>T |
| MANE Select transcript | [NM_003380](https://www.ncbi.nlm.nih.gov/nuccore/NM_003380) |
| dbSNP | [rs779204525](https://www.ncbi.nlm.nih.gov/snp/rs779204525/) |
| Variant type | single nucleotide variant |
| Location | chr10:17229445-17229445 (GRCh38) |
| ClinVar | [VCV806442](https://www.ncbi.nlm.nih.gov/clinvar/variation/806442/) |

**All HGVS expressions:** `NC_000010.10:g.17271444C>T`, `NC_000010.11:g.17229445C>T`, `NG_012413.1:g.6187C>T`, `NM_003380.5:c.23C>T`, `NR_108061.1:n.541G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.211)
- REVEL 0.334 (indeterminate)
- SaProt LLR -10.336 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.143, GERP -0.081, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.5**. 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 1.06** across the covering region of the MANE Select transcript (17,229,423–17,229,678), spanning 255 bp. Chi-square p 0.5. 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 **0.00**, acceptor gain **0.22**, donor gain **0.01**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.01**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.00. 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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,082 in the highest group · 3/1,606,426 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**VIM** population constraint: LOEUF 0.542, pLI 0.86008, missense-Z 0.8557. *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 **8** lies in a modified residue (phosphoserine); the 'disordered' region; the 'head' region.

AlphaFold model confidence (whole protein): pLDDT 78.05, 52% of residues very-high.

**26 experimental structure(s)** (PDB): [1GK4](https://www.rcsb.org/structure/1GK4), [1GK6](https://www.rcsb.org/structure/1GK6), [1GK7](https://www.rcsb.org/structure/1GK7), [3G1E](https://www.rcsb.org/structure/3G1E), [3KLT](https://www.rcsb.org/structure/3KLT), [3S4R](https://www.rcsb.org/structure/3S4R).

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

*Describes the biological roles of VIM (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:** VIM's established molecular role includes double-stranded RNA binding. p.Ser8Leu falls in the disordered region. In Reactome, VIM is annotated in disease pathway(s) including **Dengue Virus Genome Translation and Replication**, **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** VIM loss or alteration is curated in [Dengue Virus Genome Translation and Replication](https://reactome.org/content/detail/R-HSA-9918487), [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

VIM participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus Genome Translation and Replication](https://reactome.org/content/detail/R-HSA-9918487) | curated |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Aggrephagy](https://reactome.org/content/detail/R-HSA-9646399) | curated |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | curated |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |
| [Chaperone Mediated Autophagy](https://reactome.org/content/detail/R-HSA-9613829) | electronic |
| [Late endosomal microautophagy](https://reactome.org/content/detail/R-HSA-9615710) | electronic |

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

**Molecular function:** double-stranded RNA binding, structural constituent of cytoskeleton, protein domain specific binding, identical protein binding, molecular adaptor activity, scaffold protein binding.

**Biological process:** positive regulation of collagen biosynthetic process, regulation of mRNA stability, cellular response to lipopolysaccharide, cellular response to muramyl dipeptide.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-12-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-01 |

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

## Similar variants {#similar}

Related VIM variant pages (same residue, condition, or type): [VIM p.Arg45His](/variant/vim-p-arg45his), [VIM p.Asp360Glu](/variant/vim-p-asp360glu), [VIM p.Leu164Val](/variant/vim-p-leu164val), [VIM p.Thr458Ala](/variant/vim-p-thr458ala), [VIM p.Val272Ile](/variant/vim-p-val272ile), [VIM c.1008+18A>G](/variant/vim-c-1008-plus-18a-g), [VIM c.1008+99G>A](/variant/vim-c-1008-plus-99g-a), [VIM c.1009-10C>T](/variant/vim-c-1009-minus-10c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 806442). 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.*