# NM_133493.5(CD109):c.1442C>T (p.Ser481Leu)

https://sugi.bio/variant/cd109-p-ser481leu

## Summary

**CD109 p.Ser481Leu (c.1442C>T)** is classified **Uncertain significance** in CD109 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.0662); Very rare (popmax 0.0017%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs201376556 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0017%, nfe)

## For patients & families {#patients}

This is a change in the CD109 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CD109](https://sugi.bio/atlas/gene/CD109/) |
| Protein change (HGVS p.) | p.Ser481Leu |
| Coding change (HGVS c.) | c.1442C>T |
| MANE Select transcript | [NM_133493](https://www.ncbi.nlm.nih.gov/nuccore/NM_133493) |
| dbSNP | [rs201376556](https://www.ncbi.nlm.nih.gov/snp/rs201376556/) |
| Variant type | single nucleotide variant |
| Location | chr6:73766955-73766955 (GRCh38) |
| ClinVar | [VCV3140277](https://www.ncbi.nlm.nih.gov/clinvar/variation/3140277/) |

**All HGVS expressions:** `LRG_1002:g.76171C>T`, `LRG_1002t1:c.1442C>T`, `NC_000006.11:g.74476678C>T`, `NC_000006.12:g.73766955C>T`, `NG_033971.1:g.76171C>T`, `NM_001159587.3:c.1442C>T`, `NM_001159588.3:c.1211C>T`, `NM_133493.5:c.1442C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0662)
- REVEL 0.215 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.354 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.012, GERP 0.211, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.99**. 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 1.02** across the covering region of the MANE Select transcript (73,696,216–73,823,630), spanning 127,414 bp. Chi-square p 0.4. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.63 acceptor loss), 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.*
- Pangolin: Δ**0.34** (loss), gain 0.00 / loss 0.34. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0017%** (nfe) · FAF95 0.00111% · FAF99 0.0009% · 20/1,179,528 in the highest group · 75/1,612,886 alleles overall — very rare (popmax 0.0017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0782% | 1,278 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,613 |
| European (non-Finnish) (grpmax) | 0.0017% | 58,977 |
| South Asian | 0.0011% | 90,910 |

Finnish 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}

**CD109** population constraint: LOEUF 1.092, pLI 5.7787e-25, missense-Z -0.00159. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **481** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 81.42, 31% of residues very-high.

**3 experimental structure(s)** (PDB): [8S3O](https://www.rcsb.org/structure/8S3O), [9FX2](https://www.rcsb.org/structure/9FX2), [9FX3](https://www.rcsb.org/structure/9FX3).

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

*Describes the biological roles of CD109 (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}

CD109 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | other |
| [Post-translational modification: synthesis of GPI-anchored proteins](https://reactome.org/content/detail/R-HSA-163125) | other |

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

**Biological process:** negative regulation of transforming growth factor beta receptor signaling pathway, negative regulation of wound healing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-20 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD109 variant pages (same residue, condition, or type): [CD109 p.Gln416Glu](/variant/cd109-p-gln416glu), [CD109 p.Ile206Val](/variant/cd109-p-ile206val), [CD109 p.Ala1104Val](/variant/cd109-p-ala1104val), [CD109 p.Ala1115Gly](/variant/cd109-p-ala1115gly), [CD109 p.Ala1148Gly](/variant/cd109-p-ala1148gly), [CD109 p.Ala1190Pro](/variant/cd109-p-ala1190pro), [CD109 p.Ala1196Asp](/variant/cd109-p-ala1196asp), [CD109 p.Ala1196Val](/variant/cd109-p-ala1196val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3140277). 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.*