# NM_001081550.2(THOC2):c.4767G>A (p.Ser1589=)

https://sugi.bio/variant/thoc2-p-ser1589

## Summary

**THOC2 p.Ser1589= (c.4767G>A)** is classified **Benign** in THOC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-08-14). Ultra-rare (popmax 0.0221%, nfe).

**At a glance:** Benign · review: Single submitter · rsID rs369296561 · 2 submitters · ultra-rare (popmax 0.0221%, nfe)

## For patients & families {#patients}

This is a change in the THOC2 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [THOC2](https://sugi.bio/atlas/gene/THOC2/) |
| Protein change (HGVS p.) | p.Ser1589= |
| Coding change (HGVS c.) | c.4767G>A |
| MANE Select transcript | [NM_001081550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001081550) |
| dbSNP | [rs369296561](https://www.ncbi.nlm.nih.gov/snp/rs369296561/) |
| Variant type | single nucleotide variant |
| Location | chrX:123610951-123610951 (GRCh38) |
| ClinVar | [VCV764241](https://www.ncbi.nlm.nih.gov/clinvar/variation/764241/) |

**All HGVS expressions:** `NC_000023.10:g.122744802C>T`, `NC_000023.11:g.123610951C>T`, `NG_021468.1:g.127103G>A`, `NM_001081550.2:c.4767G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.606, GERP -3.69, phastCons 0.013 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.551**. 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 deltas (raw): acceptor loss **0.14**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.14**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0221%** (nfe) · FAF95 0.0196% · FAF99 0.0186% · 198/893,913 in the highest group · 206/1,207,028 alleles overall — ultra-rare (popmax 0.0221%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0221% | 4,515 |
| Admixed American | 0.00663% | 15,091 |
| Remaining individuals (not grpmax-eligible) | 0.00421% | 23,750 |
| African / African-American | 0.00351% | 28,485 |
| South Asian | 0.00178% | 56,255 |

*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):

- **X-linked complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}

Residue **1589** lies in the 'charged domain' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.83, 33% of residues very-high.

**4 experimental structure(s)** (PDB): [7APK](https://www.rcsb.org/structure/7APK), [7ZNK](https://www.rcsb.org/structure/7ZNK), [7ZNL](https://www.rcsb.org/structure/7ZNL), [8R7L](https://www.rcsb.org/structure/8R7L).

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

*Describes the biological roles of THOC2 (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}

THOC2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transport of Mature mRNA derived from an Intron-Containing Transcript](https://reactome.org/content/detail/R-HSA-159236) | curated |
| [mRNA 3'-end processing](https://reactome.org/content/detail/R-HSA-72187) | curated |
| [RNA Polymerase II Transcription Termination](https://reactome.org/content/detail/R-HSA-73856) | other |

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

**Biological process:** mRNA export from nucleus, poly(A)+ mRNA export from nucleus, neuron development, generation of neurons.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-14.

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

**Submission history:** 2 submissions (2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-08-14 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not provided, Thyroid cancer, nonmedullary, 1, none provided.

## Similar variants {#similar}

Related THOC2 variant pages (same residue, condition, or type): [THOC2 p.Ser1589Leu](/variant/thoc2-p-ser1589leu), [THOC2 p.Cys615Tyr](/variant/thoc2-p-cys615tyr), [THOC2 p.Thr696Ile](/variant/thoc2-p-thr696ile), [THOC2 p.Ala912Pro](/variant/thoc2-p-ala912pro), [THOC2 p.Arg1307Trp](/variant/thoc2-p-arg1307trp), [THOC2 p.Arg1468Lys](/variant/thoc2-p-arg1468lys), [THOC2 p.Asn208Ser](/variant/thoc2-p-asn208ser), [THOC2 p.Asn414Tyr](/variant/thoc2-p-asn414tyr).

### 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 764241). 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.*