# NM_020442.6(VARS2):c.1511C>T (p.Pro504Leu)

https://sugi.bio/variant/vars2-p-pro504leu

## Summary

**VARS2 p.Pro504Leu (c.1511C>T)** is classified **Uncertain significance** in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-31). AlphaMissense: ambiguous (0.5211); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the VARS2 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 | [VARS2](https://sugi.bio/atlas/gene/VARS2/) |
| Protein change (HGVS p.) | p.Pro504Leu |
| Coding change (HGVS c.) | c.1511C>T |
| MANE Select transcript | [NM_020442](https://www.ncbi.nlm.nih.gov/nuccore/NM_020442) |
| Variant type | single nucleotide variant |
| Location | chr6:30921096-30921096 (GRCh38) |
| ClinVar | [VCV3897331](https://www.ncbi.nlm.nih.gov/clinvar/variation/3897331/) |

**All HGVS expressions:** `NC_000006.11:g.30888873C>T`, `NC_000006.12:g.30921096C>T`, `NG_034224.1:g.11889C>T`, `NM_001167733.3:c.1091C>T`, `NM_001167734.2:c.1601C>T`, `NM_020442.6:c.1511C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5211) — no call either way
- REVEL 0.472 (indeterminate)
- SaProt LLR -10.283 (damaging)
- Conservation: phyloP 7.51, GERP 1.76, phastCons 1 — highly conserved
- CADD: **PHRED 25.3**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,856 in the highest group · 1/1,613,830 alleles overall — very rare (popmax 8.48e-05%, 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}


Curated gene–disease validity (ClinGen):

- **neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy** — Definitive (AR)
- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.12, 65% of residues very-high.

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

*Describes the biological roles of VARS2 (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:** VARS2's established molecular role includes valine-tRNA ligase activity.


### Pathways affected {#pathways}

VARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cytosolic tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379716) | curated |

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

**Molecular function:** valine-tRNA ligase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-31 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related VARS2 variant pages (same residue, condition, or type): [VARS2 p.Pro504=](/variant/vars2-p-pro504), [VARS1 p.Arg1058Gln](/variant/vars1-p-arg1058gln), [VARS1 p.Arg1119Cys](/variant/vars1-p-arg1119cys), [VARS1 p.Arg1208Ter](/variant/vars1-p-arg1208ter), [VARS1 p.Gln1039Ter](/variant/vars1-p-gln1039ter), [VARS1 p.Trp790Ter](/variant/vars1-p-trp790ter), [VARS2 c.1480-2A>G](/variant/vars2-c-1480-minus-2a-g), [VARS2 c.2467-2A>G](/variant/vars2-c-2467-minus-2a-g).

### 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 3897331). 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.*