# NM_000095.3(COMP):c.768C>A (p.Ala256=)

https://sugi.bio/variant/comp-p-ala256

## Summary

**COMP p.Ala256= (c.768C>A)** is classified **Likely benign** in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-22). Ultra-rare (popmax 0.0136%, eas); Associated with connective tissue disorder.

**At a glance:** Likely benign · review: Single submitter · rsID rs369897902 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0136%, eas)

## For patients & families {#patients}

This is a change in the COMP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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/) |
| Protein change (HGVS p.) | p.Ala256= |
| Coding change (HGVS c.) | c.768C>A |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs369897902](https://www.ncbi.nlm.nih.gov/snp/rs369897902/) |
| Variant type | single nucleotide variant |
| Location | chr19:18788509-18788509 (GRCh38) |
| ClinVar | [VCV1702394](https://www.ncbi.nlm.nih.gov/clinvar/variation/1702394/) |

**All HGVS expressions:** `NC_000019.10:g.18788509G>T`, `NC_000019.9:g.18899318G>T`, `NG_007070.1:g.7797C>A`, `NG_007070.2:g.7796C>A`, `NM_000095.3:c.768C>A`

## 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 **acceptor gain** (Δ 0.43) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.551, GERP -4.02 — fast-evolving / accelerated position
- CADD: **PHRED 14.13**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0136%** (eas) · FAF95 0.00587% · FAF99 0.00399% · 6/44,160 in the highest group · 6/1,602,202 alleles overall — ultra-rare (popmax 0.0136%, 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}

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

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

## Protein context {#protein}

Residue **256** lies in the egf-like 4 domain.

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. p.Ala256= falls in the egf-like 4 domain.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Connective tissue disorder, Connective tissue disease.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Ala256Thr](/variant/comp-p-ala256thr), [COMP c.217+4A>G](/variant/comp-c-217-plus-4a-g), [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).

### 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 1702394). 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.*