# NM_000361.3(THBD):c.1483C>T (p.Pro495Ser)

https://sugi.bio/variant/thbd-p-pro495ser

## Summary

**THBD p.Pro495Ser (c.1483C>T)** is classified **Conflicting classifications of pathogenicity** in THBD (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.088); Rare (popmax 0.174%, nfe); Associated with thrombomodulin-related bleeding disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1800578 · 10 submitters · 3 linked conditions · AlphaMissense likely benign · rare (popmax 0.174%, nfe)

## For patients & families {#patients}

This is a change in the THBD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 submitters, 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.Pro495Ser |
| Coding change (HGVS c.) | c.1483C>T |
| MANE Select transcript | [NM_000361](https://www.ncbi.nlm.nih.gov/nuccore/NM_000361) |
| dbSNP | [rs1800578](https://www.ncbi.nlm.nih.gov/snp/rs1800578/) |
| Variant type | single nucleotide variant |
| Location | chr20:23048022-23048022 (GRCh38) |
| ClinVar | [VCV12720](https://www.ncbi.nlm.nih.gov/clinvar/variation/12720/) |

**All HGVS expressions:** `LRG_168:g.6643C>T`, `LRG_168t1:c.1483C>T`, `NC_000020.10:g.23028659G>A`, `NC_000020.11:g.23048022G>A`, `NG_012027.1:g.6643C>T`, `NM_000361.3:c.1483C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.088)
- REVEL 0.278 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.583 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.676, GERP -2.51 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.612**. 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.*
- Regional missense constraint: **o/e 1.04** across the covering region of the MANE Select transcript (23,047,780–23,049,504), spanning 1,724 bp. Chi-square p 0.25. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.174%** (nfe) · FAF95 0.168% · FAF99 0.165% · 2,055/1,178,310 in the highest group · 2,203/1,609,724 alleles overall — rare (popmax 0.174%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.19% | 528 |
| European (non-Finnish) (grpmax) | 0.174% | 573 |
| Finnish (not grpmax-eligible) | 0.0207% | 4,836 |
| African / African-American | 0.02% | 5,001 |
| Admixed American | 0.00168% | 59,530 |
| South Asian | 0.0011% | 90,618 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **495** lies in the 'involved in alpha-l/beta-2 and alpha-m/beta-2 integrin binding' region; the 'disordered' region; a UniProt-annotated variant site (in ahus6; cells transfected with the mutant are less effective in converting c3b to ic3b on the cell surface after complement activation).

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.Pro495Ser falls in the involved in alpha-l/beta-2 and alpha-m/beta-2 integrin binding region.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (4 Likely benign, 3 Uncertain significance, 1 Benign, 1 risk factor, 1 Pathogenic).

**Submission history:** 10 submissions (2009–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2024-03-01 |
| OMIM | risk factor | no assertion criteria provided | literature only | 2009-07-23 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-02-05 |
| Sydney Genome Diagnostics, Children's Hospital Westmead | Pathogenic | no assertion criteria provided | clinical testing | 2018-09-06 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-13 |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Uncertain significance | criteria provided, single submitter | clinical testing |  |
| Genomenon, Inc, Genomenon, Inc | Likely benign | criteria provided, single submitter | curation | 2025-09-22 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-16 |

## Associated conditions {#conditions}

[thrombomodulin-related bleeding disorder](https://sugi.bio/atlas/disease/thrombomodulin-related-bleeding-disorder/), [atypical hemolytic-uremic syndrome with thrombomodulin anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-thrombomodulin-anomaly/), [atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Thrombomodulin-related bleeding disorder, Atypical hemolytic-uremic syndrome with thrombomodulin anomaly, not provided, Atypical hemolytic-uremic syndrome, THBD-related disorder, not specified, THBD-related condition, AllHighlyPenetrant, Thrombophilia due to thrombomodulin defect, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6.

## Similar variants {#similar}

Related THBD variant pages (same residue, condition, or type): [THBD p.Cys537Ter](/variant/thbd-p-cys537ter), [THBD p.Ala139Ser](/variant/thbd-p-ala139ser), [THBD p.Ala255Pro](/variant/thbd-p-ala255pro), [THBD p.Ala271Thr](/variant/thbd-p-ala271thr), [THBD p.Ala284Gly](/variant/thbd-p-ala284gly), [THBD p.Ala395Val](/variant/thbd-p-ala395val), [THBD p.Ala471Thr](/variant/thbd-p-ala471thr), [THBD p.Ala545Thr](/variant/thbd-p-ala545thr).

### 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 12720). 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.*