# NM_001081550.2(THOC2):c.4338A>G (p.Pro1446=)

https://sugi.bio/variant/thoc2-p-pro1446

## Summary

**THOC2 p.Pro1446= (c.4338A>G)** is classified **Benign/Likely benign** in THOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-18). Rare (popmax 0.572%, sas); Associated with X-linked intellectual disability-short stature-overweight syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs367878305 · 2 submitters · 1 linked condition · rare (popmax 0.572%, sas)

## For patients & families {#patients}

This is a change in the THOC2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to X-linked intellectual disability-short stature-overweight 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/0017800/index) · [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.Pro1446= |
| Coding change (HGVS c.) | c.4338A>G |
| MANE Select transcript | [NM_001081550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001081550) |
| dbSNP | [rs367878305](https://www.ncbi.nlm.nih.gov/snp/rs367878305/) |
| Variant type | single nucleotide variant |
| Location | chrX:123614163-123614163 (GRCh38) |
| ClinVar | [VCV788159](https://www.ncbi.nlm.nih.gov/clinvar/variation/788159/) |

**All HGVS expressions:** `NC_000023.10:g.122748014T>C`, `NC_000023.11:g.123614163T>C`, `NG_021468.1:g.123891A>G`, `NM_001081550.2:c.4338A>G`

## 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 5.093, GERP 2.93, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.12**. 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 (T>A, Δ0.35 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 **0.572%** (sas) · FAF95 0.519% · FAF99 0.498% · 303/53,015 in the highest group · 343/1,192,603 alleles overall — rare (popmax 0.572%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.572% | 175 |
| Remaining individuals (not grpmax-eligible) | 0.0702% | 1,424 |
| Middle Eastern | 0.0234% | 4,275 |
| African / African-American | 0.00177% | 56,650 |
| European (non-Finnish) | 0.000564% | 177,158 |

*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 **1446** 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/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-18.

**Submitter consensus:** conflicting (1 Likely benign, 1 Benign).

**Submission history:** 2 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-10-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-18 |

## Associated conditions {#conditions}

[X-linked intellectual disability-short stature-overweight syndrome](https://sugi.bio/atlas/disease/x-linked-intellectual-disability-short-stature-overweight-syndrome/).

**Reported phenotype names (ClinVar):** X-linked intellectual disability-short stature-overweight syndrome, not provided, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 12, Intellectual developmental disorder, X-linked syndromic, Kumar type, MENTAL RETARDATION, X-LINKED 35, none provided.

## Similar variants {#similar}

Related THOC2 variant pages (same residue, condition, or type): [THOC2 p.Pro1446Ser](/variant/thoc2-p-pro1446ser), [THOC2 p.Cys615Tyr](/variant/thoc2-p-cys615tyr), [THOC2 p.Thr696Ile](/variant/thoc2-p-thr696ile), [THOC2 p.Ala912Pro](/variant/thoc2-p-ala912pro), [THOC2 p.Asn208Ser](/variant/thoc2-p-asn208ser), [THOC2 p.Asp656Gly](/variant/thoc2-p-asp656gly), [THOC2 p.Gly1205Arg](/variant/thoc2-p-gly1205arg), [THOC2 p.Pro1416Ser](/variant/thoc2-p-pro1416ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 788159). 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.*