# NM_014285.7(EXOSC2):c.691C>T (p.Arg231Ter)

https://sugi.bio/variant/exosc2-p-arg231ter

## Summary

**EXOSC2 p.Arg231Ter (c.691C>T)** is classified **Conflicting classifications of pathogenicity** in EXOSC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0173%, afr); Associated with retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs149299789 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0173%, afr)

## For patients & families {#patients}

This is a change in the EXOSC2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome.

*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/0017903/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EXOSC2](https://sugi.bio/atlas/gene/EXOSC2/) |
| Protein change (HGVS p.) | p.Arg231Ter |
| Coding change (HGVS c.) | c.691C>T |
| MANE Select transcript | [NM_014285](https://www.ncbi.nlm.nih.gov/nuccore/NM_014285) |
| dbSNP | [rs149299789](https://www.ncbi.nlm.nih.gov/snp/rs149299789/) |
| Variant type | single nucleotide variant |
| Location | chr9:130703071-130703071 (GRCh38) |
| ClinVar | [VCV1496327](https://www.ncbi.nlm.nih.gov/clinvar/variation/1496327/) |

**All HGVS expressions:** `NC_000009.11:g.133578458C>T`, `NC_000009.12:g.130703071C>T`, `NM_001282708.1:c.613C>T`, `NM_001282709.1:c.601C>T`, `NM_014285.7:c.691C>T`, `NR_104230.1:n.1229C>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 3.953, GERP 2.26, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.009, pLI 5.217e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 43.0**. 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, Δ0.97 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 **0.0173%** (afr) · FAF95 0.0106% · FAF99 0.00997% · 13/74,982 in the highest group · 160/1,613,528 alleles overall — ultra-rare (popmax 0.0173%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0173% | 5,768 |
| European (non-Finnish) | 0.0123% | 8,136 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,246 |

*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}

**EXOSC2** population constraint: LOEUF 1.009, pLI 5.217e-08, missense-Z 0.68158. *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):

- **retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome** — Limited (AR)

## Protein context {#protein}

Residue **231** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.25, 31% 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 EXOSC2 (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.*


### Pathways affected {#pathways}

EXOSC2 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}

**Biological process:** RNA processing, RNA catabolic process, positive regulation of cell growth.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-02.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely Pathogenic).

**Submission history:** 3 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-02 |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-01 |

## Associated conditions {#conditions}

[retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome](https://sugi.bio/atlas/disease/retinitis-pigmentosa-hearing-loss-premature-aging-short-stature-facial-dysmorphism-syndrome/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, not provided, Short stature, hearing loss, retinitis pigmentosa, and distinctive facies, none provided.

## Similar variants {#similar}

Related EXOSC2 variant pages (same residue, condition, or type): [EXOSC2 p.Lys65Asn](/variant/exosc2-p-lys65asn), [EXOSC2 p.Met5Val](/variant/exosc2-p-met5val), [EXOSC2 p.Tyr206His](/variant/exosc2-p-tyr206his), [EXOSC2 p.Gly198Asp](/variant/exosc2-p-gly198asp), [EXOSC2 p.Trp204Ter](/variant/exosc2-p-trp204ter), [EXOSC2 c.673-1G>T](/variant/exosc2-c-673-minus-1g-t), [EXOSC2 c.801+1G>A](/variant/exosc2-c-801-plus-1g-a), [EXOSC2 p.Arg87Gln](/variant/exosc2-p-arg87gln).

### 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 1496327). 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.*