# NM_000088.4(COL1A1):c.183C>T (p.Cys61=)

https://sugi.bio/variant/col1a1-p-cys61

## Summary

**COL1A1 p.Cys61= (c.183C>T)** is classified **Benign/Likely benign** in COL1A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-25). Very rare (popmax 0.00891%, eas); Associated with osteogenesis imperfecta type 1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs755126464 · 2 submitters · 1 linked condition · very rare (popmax 0.00891%, eas)

## For patients & families {#patients}

This is a change in the COL1A1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to osteogenesis imperfecta type 1.

*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/0008694/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL1A1](https://sugi.bio/atlas/gene/COL1A1/) |
| Protein change (HGVS p.) | p.Cys61= |
| Coding change (HGVS c.) | c.183C>T |
| MANE Select transcript | [NM_000088](https://www.ncbi.nlm.nih.gov/nuccore/NM_000088) |
| dbSNP | [rs755126464](https://www.ncbi.nlm.nih.gov/snp/rs755126464/) |
| Variant type | single nucleotide variant |
| Location | chr17:50199868-50199868 (GRCh38) |
| ClinVar | [VCV2452655](https://www.ncbi.nlm.nih.gov/clinvar/variation/2452655/) |

**All HGVS expressions:** `LRG_1:g.6772C>T`, `LRG_1t1:c.183C>T`, `NC_000017.10:g.48277229G>A`, `NC_000017.11:g.50199868G>A`, `NG_007400.1:g.6772C>T`, `NM_000088.4:c.183C>T`

## 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 0.362, GERP -3.76, phastCons 0.441 — weakly conserved position
- CADD: **PHRED 12.69**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for COL1A1 (1,242 scored positions, the nearest 15 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00891%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,894 in the highest group · 4/1,614,088 alleles overall — very rare (popmax 0.00891%, eas).

*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}

**COL1A1** population constraint: LOEUF 0.159, pLI 1, missense-Z 5.7881; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **Caffey disease** — Definitive (AD)
- **osteogenesis imperfecta** — Definitive (AD)
- **COL1A1-related Ehlers-Danlos syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **61** lies in the vwfc domain.

AlphaFold model confidence (whole protein): pLDDT 54.26, 18% of residues very-high.

**14 experimental structure(s)** (PDB): [1Q7D](https://www.rcsb.org/structure/1Q7D), [2LLP](https://www.rcsb.org/structure/2LLP), [3EJH](https://www.rcsb.org/structure/3EJH), [3GXE](https://www.rcsb.org/structure/3GXE), [5CTD](https://www.rcsb.org/structure/5CTD), [5CTI](https://www.rcsb.org/structure/5CTI) — incl. mutant structure 7E7B.

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

*Describes the biological roles of COL1A1 (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:** COL1A1's established molecular role includes protease binding. p.Cys61= falls in the vwfc domain. In Reactome, COL1A1 is annotated in disease pathway(s) including **Defective VWF binding to collagen type I **, **Defective VWF cleavage by ADAMTS13 variant**.

**Disease mechanism (Reactome):** COL1A1 loss or alteration is curated in [Defective VWF binding to collagen type I ](https://reactome.org/content/detail/R-HSA-9845622), [Defective VWF cleavage by ADAMTS13 variant](https://reactome.org/content/detail/R-HSA-9845621), [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298).

### Pathways affected {#pathways}

COL1A1 participates in **27 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective VWF binding to collagen type I ](https://reactome.org/content/detail/R-HSA-9845622) | curated |
| ⚕ [Defective VWF cleavage by ADAMTS13 variant](https://reactome.org/content/detail/R-HSA-9845621) | curated |
| ⚕ [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298) | curated |
| ⚕ [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620) | curated |
| ⚕ [Enhanced cleavage of VWF variant by ADAMTS13](https://reactome.org/content/detail/R-HSA-9845619) | curated |
| [Anchoring fibril formation](https://reactome.org/content/detail/R-HSA-2214320) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |
| [Collagen chain trimerization](https://reactome.org/content/detail/R-HSA-8948216) | curated |
| [Crosslinking of collagen fibrils](https://reactome.org/content/detail/R-HSA-2243919) | curated |
| [Developmental Lineage of Pancreatic Ductal Cells](https://reactome.org/content/detail/R-HSA-9925563) | curated |
| [Developmental Lineage of Pancreatic Endocrine Mid Progenitor Cells](https://reactome.org/content/detail/R-HSA-9981148) | curated |
| [Fibronectin matrix formation](https://reactome.org/content/detail/R-HSA-1566977) | curated |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | curated |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |
| [Platelet Adhesion to exposed collagen](https://reactome.org/content/detail/R-HSA-75892) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [Scavenging by Class A Receptors](https://reactome.org/content/detail/R-HSA-3000480) | electronic |
| [Syndecan interactions](https://reactome.org/content/detail/R-HSA-3000170) | electronic |

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

**Molecular function:** protease binding, extracellular matrix structural constituent conferring tensile strength, identical protein binding, platelet-derived growth factor binding.

**Biological process:** skeletal system development, blood vessel development, visual perception, sensory perception of sound, positive regulation of epithelial to mesenchymal transition, collagen fibril organization.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-01-25.

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

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2022-12-14 |

## Associated conditions {#conditions}

[osteogenesis imperfecta type 1](https://sugi.bio/atlas/disease/osteogenesis-imperfecta-type-1/).

**Reported phenotype names (ClinVar):** Osteogenesis imperfecta type I, Cardiovascular phenotype, OI, TYPE I, OSTEOGENESIS IMPERFECTA TARDA, OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE, Lobstein disease, Osteogenesis imperfecta type 1, Lobstein's Disease, Classic Non-deforming Osteogenesis Imperfecta with Blue Sclerae.

## Same-residue context {#hotspot}

Residue **61** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [COL1A1 p.Cys61Trp](/variant/col1a1-p-cys61trp), [COL1A1 p.Cys61Tyr](/variant/col1a1-p-cys61tyr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related COL1A1 variant pages (same residue, condition, or type): [COL1A1 p.Cys61Trp](/variant/col1a1-p-cys61trp), [COL1A1 p.Cys61Tyr](/variant/col1a1-p-cys61tyr), [COL1A1 c.1003-1G>A](/variant/col1a1-c-1003-minus-1g-a), [COL1A1 c.103+1G>A](/variant/col1a1-c-103-plus-1g-a), [COL1A1 c.103+2T>C](/variant/col1a1-c-103-plus-2t-c), [COL1A1 c.104-1G>T](/variant/col1a1-c-104-minus-1g-t), [COL1A1 c.104-2A>G](/variant/col1a1-c-104-minus-2a-g), [COL1A1 c.1056+1G>A](/variant/col1a1-c-1056-plus-1g-a).

### 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 2452655). 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.*