# NM_003380.5(VIM):c.490C>G (p.Leu164Val)

https://sugi.bio/variant/vim-p-leu164val

## Summary

**VIM p.Leu164Val (c.490C>G)** is classified **Uncertain significance** in VIM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-27). AlphaMissense: likely benign (0.1339); Ultra-rare (popmax 0.0334%, afr); Associated with cataract 30.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0334%, afr)

## 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 2 submitters, and is linked to cataract 30.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024545/index) · [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.Leu164Val |
| Coding change (HGVS c.) | c.490C>G |
| MANE Select transcript | [NM_003380](https://www.ncbi.nlm.nih.gov/nuccore/NM_003380) |
| Variant type | single nucleotide variant |
| Location | chr10:17229912-17229912 (GRCh38) |
| ClinVar | [VCV4198802](https://www.ncbi.nlm.nih.gov/clinvar/variation/4198802/) |

**All HGVS expressions:** `NC_000010.10:g.17271911C>G`, `NC_000010.11:g.17229912C>G`, `NG_012413.1:g.6654C>G`, `NG_182899.1:g.43C>G`, `NM_003380.5:c.490C>G`, `NR_108061.1:n.74G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1339)
- REVEL 0.374 (indeterminate)
- SaProt LLR -9.094 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.32) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.459, GERP -2.4, phastCons 1 — weakly conserved position
- CADD: **PHRED 21.2**. 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 0.90** across the covering region of the MANE Select transcript (17,229,788–17,237,268), spanning 7,480 bp. Chi-square p 0.038. 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 **0.00**, donor gain **0.32**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.32**.
- Population frequency (gnomAD v4.1): grpmax **0.0334%** (afr) · FAF95 0.0231% · FAF99 0.0198% · 25/74,940 in the highest group · 25/1,612,700 alleles overall — ultra-rare (popmax 0.0334%, afr).

*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 **164** lies in the if rod domain; the 'coil 1b' 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.Leu164Val falls in the if rod domain. 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-27.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-12 |

## Associated conditions {#conditions}

[cataract 30](https://sugi.bio/atlas/disease/cataract-30/).

**Reported phenotype names (ClinVar):** Cataract 30, not specified, AllHighlyPenetrant, CATARACT 30, PULVERULENT.

## 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.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.1009-10C>T](/variant/vim-c-1009-minus-10c-t), [VIM c.1360-18G>T](/variant/vim-c-1360-minus-18g-t), [VIM c.720+18C>T](/variant/vim-c-720-plus-18c-t).

### 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 4198802). 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.*