# NM_005202.4(COL8A2):c.1764G>A (p.Ser588=)

https://sugi.bio/variant/col8a2-p-ser588

## Summary

**COL8A2 p.Ser588= (c.1764G>A)** is classified **Benign** in COL8A2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-08). Rare (popmax 0.197%, mid).

**At a glance:** Benign · review: Single submitter · 2 submitters · rare (popmax 0.197%, mid)

## For patients & families {#patients}

This is a change in the COL8A2 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [COL8A2](https://sugi.bio/atlas/gene/COL8A2/) |
| Protein change (HGVS p.) | p.Ser588= |
| Coding change (HGVS c.) | c.1764G>A |
| MANE Select transcript | [NM_005202](https://www.ncbi.nlm.nih.gov/nuccore/NM_005202) |
| Variant type | single nucleotide variant |
| Location | chr1:36097917-36097917 (GRCh38) |
| ClinVar | [VCV3645494](https://www.ncbi.nlm.nih.gov/clinvar/variation/3645494/) |

**All HGVS expressions:** `NC_000001.10:g.36563518C>T`, `NC_000001.11:g.36097917C>T`, `NG_016245.2:g.32168G>A`, `NG_090556.1:g.544C>T`, `NM_001294347.2:c.1569G>A`, `NM_005202.4:c.1764G>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 0.80) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -7.08, GERP -4.18 — fast-evolving / accelerated position
- CADD: **PHRED 18.77**. 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 **0.16**, donor loss **0.00**, acceptor gain **0.80**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.80**, donor gain **0.00**.
- Pangolin: Δ**0.79** (gain), gain 0.79 / loss 0.00. 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 **0.197%** (mid) · FAF95 0.114% · FAF99 0.0893% · 12/6,078 in the highest group · 401/1,611,706 alleles overall — rare (popmax 0.197%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.197% | 507 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0574% | 1,741 |
| Remaining individuals (not grpmax-eligible) | 0.0432% | 2,313 |
| Admixed American | 0.0367% | 2,726 |
| European (non-Finnish) | 0.0265% | 3,770 |
| East Asian | 0.0111% | 8,979 |
| South Asian | 0.00439% | 22,770 |
| African / African-American | 0.00133% | 74,930 |

*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}

**COL8A2** population constraint: LOEUF 1.139, pLI 5.589e-05, missense-Z 0.29122. *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 **588** lies in the c1q domain; the 'nonhelical region (nc1)' region.

AlphaFold model confidence (whole protein): pLDDT 58.03, 21% of residues very-high.

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

*Describes the biological roles of COL8A2 (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}

COL8A2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | 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 |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-08.

**Submitter consensus:** unanimous (1/1 Benign).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2024-10-08 |

**Reported phenotype names (ClinVar):** not provided, Clear cell carcinoma of kidney, none provided.

## Similar variants {#similar}

Related COL8A2 variant pages (same residue, condition, or type): [COL8A2 p.Arg149Gln](/variant/col8a2-p-arg149gln), [COL8A2 p.Arg263Ser](/variant/col8a2-p-arg263ser), [COL8A2 p.Arg372Cys](/variant/col8a2-p-arg372cys), [COL8A2 p.Glu568Lys](/variant/col8a2-p-glu568lys), [COL8A2 p.Gly549Ser](/variant/col8a2-p-gly549ser), [COL8A2 p.Gly550Ser](/variant/col8a2-p-gly550ser), [COL8A2 p.Gly559Glu](/variant/col8a2-p-gly559glu), [COL8A2 p.Gly601Ala](/variant/col8a2-p-gly601ala).

### 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 3645494). 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.*