# NM_014000.3(VCL):c.1788A>C (p.Ser596=)

https://sugi.bio/variant/vcl-p-ser596

## Summary

**VCL p.Ser596= (c.1788A>C)** is classified **Benign/Likely benign** in VCL (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0141%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs199582103 · 8 submitters · 2 linked conditions · ultra-rare (popmax 0.0141%, nfe)

## For patients & families {#patients}

This is a change in the VCL gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, and is linked to Cardiovascular phenotype.

*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 | [VCL](https://sugi.bio/atlas/gene/VCL/) |
| Protein change (HGVS p.) | p.Ser596= |
| Coding change (HGVS c.) | c.1788A>C |
| MANE Select transcript | [NM_014000](https://www.ncbi.nlm.nih.gov/nuccore/NM_014000) |
| dbSNP | [rs199582103](https://www.ncbi.nlm.nih.gov/snp/rs199582103/) |
| Variant type | single nucleotide variant |
| Location | chr10:74097248-74097248 (GRCh38) |
| ClinVar | [VCV45589](https://www.ncbi.nlm.nih.gov/clinvar/variation/45589/) |

**All HGVS expressions:** `LRG_383:g.104135A>C`, `LRG_383t1:c.1788A>C`, `NC_000010.10:g.75857006A>C`, `NC_000010.11:g.74097248A>C`, `NG_008868.1:g.104135A>C`, `NM_003373.4:c.1788A>C`, `NM_014000.3:c.1788A>C`

## 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 -3.012, GERP -5.48 — fast-evolving / accelerated position
- CADD: **PHRED 9.918**. 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 (A>T, Δ0.39 acceptor gain), 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 **0.0141%** (nfe) · FAF95 0.0123% · FAF99 0.0116% · 166/1,180,014 in the highest group · 253/1,614,040 alleles overall — ultra-rare (popmax 0.0141%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.125% | 800 |
| European (non-Finnish) (grpmax) | 0.0141% | 7,109 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,414 |
| Admixed American | 0.00167% | 60,012 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**VCL** population constraint: LOEUF 0.461, pLI 0.99858, missense-Z 4.2503. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypertrophic cardiomyopathy** — Disputed (AD)
- **dilated cardiomyopathy 1W** — Strong (AD)
- **congenital heart disease** — No Known Disease Relationship (UD)

## Protein context {#protein}

Residue **596** lies in the 'n-terminal globular head' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.69, 63% of residues very-high.

**37 experimental structure(s)** (PDB): [1RKC](https://www.rcsb.org/structure/1RKC), [1RKE](https://www.rcsb.org/structure/1RKE), [1SYQ](https://www.rcsb.org/structure/1SYQ), [1TR2](https://www.rcsb.org/structure/1TR2), [1YDI](https://www.rcsb.org/structure/1YDI), [2GWW](https://www.rcsb.org/structure/2GWW) — incl. mutant structure 3VF0.

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

*Describes the biological roles of VCL (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:** VCL's established molecular role includes dystroglycan binding. p.Ser596= falls in the n-terminal globular head region. In Reactome, VCL is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** VCL loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952).

### Pathways affected {#pathways}

VCL participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |

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

**Molecular function:** dystroglycan binding, actin binding, ubiquitin protein ligase binding, alpha-catenin binding, cadherin binding, molecular adaptor activity.

**Biological process:** morphogenesis of an epithelium, adherens junction assembly, protein localization to cell surface, apical junction assembly, regulation of focal adhesion assembly, epithelial cell-cell adhesion.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (6 Likely benign, 2 Benign).

**Submission history:** 8 submissions (2010–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2010-09-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2017-05-30 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-03-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-10-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-16 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [dilated cardiomyopathy 1W](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1w/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, not provided, Dilated cardiomyopathy 1W, VCL-related disorder, VCL-related condition, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related VCL variant pages (same residue, condition, or type): [VCL c.1176+4G>C](/variant/vcl-c-1176-plus-4g-c), [VCL c.1352+5G>A](/variant/vcl-c-1352-plus-5g-a), [VCL c.1543+1G>T](/variant/vcl-c-1543-plus-1g-t), [VCL c.1543+4A>G](/variant/vcl-c-1543-plus-4a-g), [VCL c.1743+6A>G](/variant/vcl-c-1743-plus-6a-g), [VCL c.1744-1G>T](/variant/vcl-c-1744-minus-1g-t), [VCL c.2022+5G>T](/variant/vcl-c-2022-plus-5g-t), [VCL c.2023-1G>C](/variant/vcl-c-2023-minus-1g-c).

### 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 45589). 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.*