# NM_000361.3(THBD):c.791_801del (p.Arg264fs)

https://sugi.bio/variant/thbd-p-arg264fs

## Summary

**THBD p.Arg264fs (c.791_801del)** is classified **Uncertain significance** in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). Associated with thrombomodulin-related bleeding disorder.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the THBD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to thrombomodulin-related bleeding disorder.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | THBD is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017726/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [THBD](https://sugi.bio/atlas/gene/THBD/) |
| Protein change (HGVS p.) | p.Arg264fs |
| Coding change (HGVS c.) | c.791_801del |
| MANE Select transcript | [NM_000361](https://www.ncbi.nlm.nih.gov/nuccore/NM_000361) |
| Variant type | Deletion |
| Location | chr20:23048704-23048714 (GRCh38) |
| ClinVar | [VCV4280347](https://www.ncbi.nlm.nih.gov/clinvar/variation/4280347/) |

**All HGVS expressions:** `LRG_168:g.5951_5961del`, `LRG_168t1:c.790_800del`, `NC_000020.10:g.23029342_23029352del`, `NC_000020.11:g.23048705_23048715del`, `NG_012027.1:g.5951_5961del`, `NM_000361.3:c.791_801del`

## 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 6.397, GERP 1.45, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.938, pLI 0.04961. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (1 of 1)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.

*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}

**THBD** population constraint: LOEUF 1.938, pLI 0.04961, missense-Z -1.6287. *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):

- **thrombomodulin-related bleeding disorder** — Moderate (AD)
- **thrombomodulin-related bleeding disorder** — Limited (AR)
- **atypical hemolytic-uremic syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **264** lies in the egf-like 1 domain.

AlphaFold model confidence (whole protein): pLDDT 79.35, 42% of residues very-high.

**13 experimental structure(s)** (PDB): [1ADX](https://www.rcsb.org/structure/1ADX), [1DQB](https://www.rcsb.org/structure/1DQB), [1DX5](https://www.rcsb.org/structure/1DX5), [1EGT](https://www.rcsb.org/structure/1EGT), [1FGD](https://www.rcsb.org/structure/1FGD), [1FGE](https://www.rcsb.org/structure/1FGE) — incl. mutant structure 5TO3.

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

*Describes the biological roles of THBD (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:** THBD's established molecular role includes signaling receptor activity. p.Arg264fs falls in the egf-like 1 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

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

**Molecular function:** signaling receptor activity.

**Biological process:** negative regulation of blood coagulation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2025-09-22 |

## Associated conditions {#conditions}

[thrombomodulin-related bleeding disorder](https://sugi.bio/atlas/disease/thrombomodulin-related-bleeding-disorder/).

**Reported phenotype names (ClinVar):** Thrombomodulin-related bleeding disorder, Thrombophilia due to thrombomodulin defect.

## Similar variants {#similar}

Related THBD variant pages (same residue, condition, or type): [THBD p.Pro496fs](/variant/thbd-p-pro496fs), [THBD p.Arg264His](/variant/thbd-p-arg264his), [THBD p.Ala43fs](/variant/thbd-p-ala43fs), [THBD p.Val454fs](/variant/thbd-p-val454fs), [THBD p.Asp418fs](/variant/thbd-p-asp418fs), [THBD p.Gly82fs](/variant/thbd-p-gly82fs), [THBD p.Tyr306del](/variant/thbd-p-tyr306del), [THBD c.*23_*40del](/variant/thbd-c-star-23-star-40del).

### 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 4280347). 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.*