# NM_001319074.4(RAX2):c.207G>A (p.Val69=)

https://sugi.bio/variant/rax2-p-val69

## Summary

**RAX2 p.Val69= (c.207G>A)** is classified **Likely benign** in RAX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-07). Very rare (popmax 0.00174%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs773887682 · 1 submitter · very rare (popmax 0.00174%, amr)

## For patients & families {#patients}

This is a change in the RAX2 gene that is classified as likely benign — not considered disease-causing, 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 | [RAX2](https://sugi.bio/atlas/gene/RAX2/) |
| Protein change (HGVS p.) | p.Val69= |
| Coding change (HGVS c.) | c.207G>A |
| MANE Select transcript | [NM_001319074](https://www.ncbi.nlm.nih.gov/nuccore/NM_001319074) |
| dbSNP | [rs773887682](https://www.ncbi.nlm.nih.gov/snp/rs773887682/) |
| Variant type | single nucleotide variant |
| Location | chr19:3771536-3771536 (GRCh38) |
| ClinVar | [VCV1111353](https://www.ncbi.nlm.nih.gov/clinvar/variation/1111353/) |

**All HGVS expressions:** `LRG_1200:g.5686G>A`, `LRG_1200t1:c.207G>A`, `LRG_1200t2:c.207G>A`, `NC_000019.10:g.3771536C>T`, `NC_000019.9:g.3771534C>T`, `NG_011565.1:g.5686G>A`, `NM_001319074.4:c.207G>A`, `NM_032753.4:c.207G>A`

## 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 -0.027, GERP -4.05, phastCons 0.91 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.554**. 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 (C>G, Δ0.78 donor loss), 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.*
- Pangolin: Δ**0.56** (gain), gain 0.56 / loss 0.26. SpliceAI below 0.2. 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 **0.00174%** (amr) · 1/57,508 in the highest group · 1/1,601,426 alleles overall — very rare (popmax 0.00174%, amr).

*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}

**RAX2** population constraint: LOEUF 1.525, pLI 0.05374, missense-Z -1.2231. *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 **69** lies in a DNA-binding region.

AlphaFold model confidence (whole protein): pLDDT 71.72, 33% of residues very-high.

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

*Describes the biological roles of RAX2 (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:** RAX2's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Val69= falls in a DNA-binding region.


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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific.

**Biological process:** positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-07 |

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

## Similar variants {#similar}

Related RAX2 variant pages (same residue, condition, or type): [RAX2 p.Pro52Arg](/variant/rax2-p-pro52arg), [RAX2 c.217-12C>A](/variant/rax2-c-217-minus-12c-a), [RAX2 c.*368C>T](/variant/rax2-c-star-368c-t), [RAX2 p.Ala105Val](/variant/rax2-p-ala105val), [RAX2 p.Ala109Thr](/variant/rax2-p-ala109thr), [RAX2 p.Ala160Val](/variant/rax2-p-ala160val), [RAX2 p.Ala164Val](/variant/rax2-p-ala164val), [RAX2 p.Ala180Pro](/variant/rax2-p-ala180pro).

### 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 1111353). 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.*