# NM_013435.3(RAX):c.266del (p.Pro89fs)

https://sugi.bio/variant/rax-p-pro89fs

## Summary

**RAX p.Pro89fs (c.266del)** is classified **Pathogenic** in RAX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-11-09). Very rare (popmax 0.00294%, sas); Associated with isolated microphthalmia 3.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2511488658 · 1 submitter · 1 linked condition · very rare (popmax 0.00294%, sas)

## For patients & families {#patients}

This is a change in the RAX gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to isolated microphthalmia 3.

*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/0024876/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RAX](https://sugi.bio/atlas/gene/RAX/) |
| Protein change (HGVS p.) | p.Pro89fs |
| Coding change (HGVS c.) | c.266del |
| MANE Select transcript | [NM_013435](https://www.ncbi.nlm.nih.gov/nuccore/NM_013435) |
| dbSNP | [rs2511488658](https://www.ncbi.nlm.nih.gov/snp/rs2511488658/) |
| Variant type | Deletion |
| Location | chr18:59272941-59272941 (GRCh38) |
| ClinVar | [VCV1723190](https://www.ncbi.nlm.nih.gov/clinvar/variation/1723190/) |

**All HGVS expressions:** `NC_000018.10:g.59272944del`, `NC_000018.9:g.56940176del`, `NG_013031.1:g.5453del`, `NM_013435.3:c.266del`

## 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 -2.513, GERP -3.36 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.197, pLI 0.00058285. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00294%** (sas) · FAF95 0.000488% · FAF99 0.000183% · 2/68,002 in the highest group · 2/1,457,946 alleles overall — very rare (popmax 0.00294%, sas).

*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}

**RAX** population constraint: LOEUF 1.197, pLI 0.00058285, missense-Z -1.0259; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **89** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.10, 19% of residues very-high.

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

*Describes the biological roles of RAX (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:** RAX's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Pro89fs falls in the disordered 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, sequence-specific double-stranded DNA binding.

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

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-11-09.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-11-09 |

## Associated conditions {#conditions}

[isolated microphthalmia 3](https://sugi.bio/atlas/disease/isolated-microphthalmia-3/).

**Reported phenotype names (ClinVar):** Isolated microphthalmia 3, MICROPHTHALMIA, SYNDROMIC 16.

## Similar variants {#similar}

Related RAX variant pages (same residue, condition, or type): [RAX c.*1300A>G](/variant/rax-c-star-1300a-g), [RAX c.*850C>T](/variant/rax-c-star-850c-t), [RAX p.Ala267Val](/variant/rax-p-ala267val), [RAX p.Ala72Gly](/variant/rax-p-ala72gly), [RAX p.Arg110Gly](/variant/rax-p-arg110gly), [RAX p.Arg166Pro](/variant/rax-p-arg166pro), [RAX p.Glu96Gln](/variant/rax-p-glu96gln), [RAX p.Gly237Asp](/variant/rax-p-gly237asp).

### 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 1723190). 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.*