# NM_005033.3(EXOSC9):c.270C>T (p.Phe90=)

https://sugi.bio/variant/exosc9-p-phe90

## Summary

**EXOSC9 p.Phe90= (c.270C>T)** is classified **Likely benign** in EXOSC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). Very rare (popmax 0.00834%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs766608315 · 1 submitter · very rare (popmax 0.00834%, amr)

## For patients & families {#patients}

This is a change in the EXOSC9 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 | [EXOSC9](https://sugi.bio/atlas/gene/EXOSC9/) |
| Protein change (HGVS p.) | p.Phe90= |
| Coding change (HGVS c.) | c.270C>T |
| MANE Select transcript | [NM_005033](https://www.ncbi.nlm.nih.gov/nuccore/NM_005033) |
| dbSNP | [rs766608315](https://www.ncbi.nlm.nih.gov/snp/rs766608315/) |
| Variant type | single nucleotide variant |
| Location | chr4:121802782-121802782 (GRCh38) |
| ClinVar | [VCV2084162](https://www.ncbi.nlm.nih.gov/clinvar/variation/2084162/) |

**All HGVS expressions:** `NC_000004.11:g.122723937C>T`, `NC_000004.12:g.121802782C>T`, `NG_029848.1:g.6466C>T`, `NM_001034194.2:c.270C>T`, `NM_005033.3:c.270C>T`

## 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 1.913, GERP -0.523, phastCons 1 — weakly conserved position
- CADD: **PHRED 14.42**. 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>A, Δ0.25 donor 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 **0.00834%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/59,970 in the highest group · 44/1,613,898 alleles overall — very rare (popmax 0.00834%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00834% | 11,994 |
| South Asian | 0.00329% | 30,357 |
| European (non-Finnish) | 0.00288% | 34,705 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,024 |
| African / African-American | 0.00133% | 74,908 |

*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}

**EXOSC9** population constraint: LOEUF 1.121, pLI 1.1629e-07, missense-Z -0.059334. *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 **90** lies in the 'are binding' region.

AlphaFold model confidence (whole protein): pLDDT 77.44, 57% of residues very-high.

**8 experimental structure(s)** (PDB): [2NN6](https://www.rcsb.org/structure/2NN6), [6D6Q](https://www.rcsb.org/structure/6D6Q), [6D6R](https://www.rcsb.org/structure/6D6R), [6H25](https://www.rcsb.org/structure/6H25), [9G8M](https://www.rcsb.org/structure/9G8M), [9G8N](https://www.rcsb.org/structure/9G8N).

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

*Describes the biological roles of EXOSC9 (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:** EXOSC9's established molecular role includes RNA binding. p.Phe90= falls in the are binding region.


### Pathways affected {#pathways}

EXOSC9 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ATF4 activates genes in response to endoplasmic reticulum  stress](https://reactome.org/content/detail/R-HSA-380994) | curated |
| [Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450385) | curated |
| [KSRP (KHSRP) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450604) | curated |
| [Major pathway of rRNA processing in the nucleolus and cytosol](https://reactome.org/content/detail/R-HSA-6791226) | curated |
| [Nuclear RNA decay](https://reactome.org/content/detail/R-HSA-9930044) | curated |
| [Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450513) | curated |
| [mRNA decay by 3' to 5' exoribonuclease](https://reactome.org/content/detail/R-HSA-429958) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** RNA binding, mRNA 3'-UTR AU-rich region binding.

**Biological process:** nuclear-transcribed mRNA catabolic process, RNA processing, RNA catabolic process, mRNA catabolic process, positive regulation of cell growth, nuclear mRNA surveillance.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-17.

**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 | 2025-11-17 |

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

## Similar variants {#similar}

Related EXOSC9 variant pages (same residue, condition, or type): [EXOSC9 p.Phe90Ser](/variant/exosc9-p-phe90ser), [EXOSC9 p.Arg161Ter](/variant/exosc9-p-arg161ter), [EXOSC9 p.Arg212Ter](/variant/exosc9-p-arg212ter), [EXOSC9 p.Arg229Ter](/variant/exosc9-p-arg229ter), [EXOSC9 p.Leu14Pro](/variant/exosc9-p-leu14pro), [EXOSC9 p.Ser7Ter](/variant/exosc9-p-ser7ter), [EXOSC9 c.1157-172A>G](/variant/exosc9-c-1157-minus-172a-g), [EXOSC9 p.Ala148Val](/variant/exosc9-p-ala148val).

### 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 2084162). 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.*