# NM_018714.3(COG1):c.2475C>T (p.Asp825=)

https://sugi.bio/variant/cog1-p-asp825

## Summary

**COG1 p.Asp825= (c.2475C>T)** is classified **Likely benign** in COG1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-20). Ultra-rare (popmax 0.0111%, eas); Associated with COG1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs533834836 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0111%, eas)

## For patients & families {#patients}

This is a change in the COG1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to COG1-related 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.*

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COG1](https://sugi.bio/atlas/gene/COG1/) |
| Protein change (HGVS p.) | p.Asp825= |
| Coding change (HGVS c.) | c.2475C>T |
| MANE Select transcript | [NM_018714](https://www.ncbi.nlm.nih.gov/nuccore/NM_018714) |
| dbSNP | [rs533834836](https://www.ncbi.nlm.nih.gov/snp/rs533834836/) |
| Variant type | single nucleotide variant |
| Location | chr17:73205645-73205645 (GRCh38) |
| ClinVar | [VCV3047686](https://www.ncbi.nlm.nih.gov/clinvar/variation/3047686/) |

**All HGVS expressions:** `NC_000017.10:g.71201784C>T`, `NC_000017.11:g.73205645C>T`, `NG_008971.1:g.17612C>T`, `NM_018714.3:c.2475C>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 -0.505, GERP -3.45, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.237**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.44 donor gain), 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.*
- Population frequency (gnomAD v4.1): grpmax **0.0111%** (eas) · FAF95 0.00434% · FAF99 0.00276% · 5/44,890 in the highest group · 26/1,613,814 alleles overall — ultra-rare (popmax 0.0111%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0111% | 8,978 |
| African / African-American | 0.00801% | 12,482 |
| South Asian | 0.00329% | 30,359 |
| European (non-Finnish) | 0.00102% | 98,330 |

*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}

**COG1** population constraint: LOEUF 0.718, pLI 6.1028e-11, missense-Z 1.1315; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

- **COG1-congenital disorder of glycosylation** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.82, 40% of residues very-high.

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

*Describes the biological roles of COG1 (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:** COG1 participates in disease-associated pathways. In Reactome, COG1 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** COG1 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

COG1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [Intra-Golgi traffic](https://reactome.org/content/detail/R-HSA-6811438) | curated |
| [Retrograde transport at the Trans-Golgi-Network](https://reactome.org/content/detail/R-HSA-6811440) | curated |

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

**Biological process:** retrograde transport, vesicle recycling within Golgi, Golgi organization.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-02-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-02-20 |

## Associated conditions {#conditions}

[COG1-related disorder](https://sugi.bio/atlas/disease/cog1-related-disorder/).

**Reported phenotype names (ClinVar):** COG1-related disorder, COG1-related condition.

## Similar variants {#similar}

Related COG1 variant pages (same residue, condition, or type): [COG1 p.Leu475=](/variant/cog1-p-leu475), [COG1 c.1070+5G>A](/variant/cog1-c-1070-plus-5g-a), [COG1 p.Arg336Ter](/variant/cog1-p-arg336ter), [COG1 p.Trp476Ter](/variant/cog1-p-trp476ter), [COG1 p.Ala143Thr](/variant/cog1-p-ala143thr), [COG1 p.Ala209Val](/variant/cog1-p-ala209val), [COG1 p.Ala27Ser](/variant/cog1-p-ala27ser), [COG1 p.Ala380Val](/variant/cog1-p-ala380val).

### 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 3047686). 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.*