# NM_000095.3(COMP):c.217+4A>G

https://sugi.bio/variant/comp-c-217-plus-4a-g

## Summary

**COMP c.217+4A>G** is classified **Uncertain significance** in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). Ultra-rare (popmax 0.0176%, sas); Associated with connective tissue disorder.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs779140776 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0176%, sas)

## For patients & families {#patients}

This is a change in the COMP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to connective tissue 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.*

|  |  |
| --- | --- |
| Clinical trials | 83 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COMP](https://sugi.bio/atlas/gene/COMP/) |
| Coding change (HGVS c.) | c.217+4A>G |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs779140776](https://www.ncbi.nlm.nih.gov/snp/rs779140776/) |
| Variant type | single nucleotide variant |
| Location | chr19:18790558-18790558 (GRCh38) |
| ClinVar | [VCV1702393](https://www.ncbi.nlm.nih.gov/clinvar/variation/1702393/) |

**All HGVS expressions:** `NC_000019.10:g.18790558T>C`, `NC_000019.9:g.18901367T>C`, `NG_007070.1:g.5748A>G`, `NM_000095.3:c.217+4A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.72) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.621, GERP 1.08, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.65**. 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.*
- Splice region: **donor splice region (+4, within the first 6 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 3.45**, o/e 0.73 (1 kb window 18,790,000–18,791,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.72**, acceptor gain **0.00**, donor gain **0.09**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.72**, acceptor gain **0.00**, donor gain **0.09**.
- Pangolin: Δ**0.66** (loss), gain 0.14 / loss 0.66. Agrees with SpliceAI. 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 **0.0176%** (sas) · FAF95 0.011% · FAF99 0.00888% · 16/91,086 in the highest group · 17/1,613,594 alleles overall — ultra-rare (popmax 0.0176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0176% | 5,693 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,468 |

*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}

**COMP** population constraint: LOEUF 1.073, pLI 1.6355e-24, missense-Z 1.5119; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **COMP-related skeletal dysplasia** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.60, 67% of residues very-high.

**1 experimental structure(s)** (PDB): [3FBY](https://www.rcsb.org/structure/3FBY).

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

*Describes the biological roles of COMP (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:** COMP's established molecular role includes protease binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |

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

**Molecular function:** protease binding, calcium ion binding, collagen binding, heparin binding, proteoglycan binding, heparan sulfate proteoglycan binding.

**Biological process:** negative regulation of apoptotic process, protein homooligomerization, limb development, cartilage homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-31.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-03-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-31 |

## Associated conditions {#conditions}

[connective tissue disorder](https://sugi.bio/atlas/disease/connective-tissue-disorder/).

**Reported phenotype names (ClinVar):** Connective tissue disorder, not provided, Connective tissue disease, none provided.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Ser444Cys](/variant/comp-p-ser444cys), [COMP c.2227+8G>A](/variant/comp-c-2227-plus-8g-a), [COMP p.Ala171Thr](/variant/comp-p-ala171thr), [COMP p.Arg718=](/variant/comp-p-arg718), [COMP p.Asn386Asp](/variant/comp-p-asn386asp), [COMP p.Asn652=](/variant/comp-p-asn652), [COMP p.Phe137Ser](/variant/comp-p-phe137ser), [COMP p.Asp4Ala](/variant/comp-p-asp4ala).

### 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 1702393). 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.*