# NM_031431.4(COG3):c.386A>C (p.Gln129Pro)

https://sugi.bio/variant/cog3-p-gln129pro

## Summary

**COG3 p.Gln129Pro (c.386A>C)** is classified **Uncertain significance** in COG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.353); Ultra-rare (popmax 0.012%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the COG3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [COG3](https://sugi.bio/atlas/gene/COG3/) |
| Protein change (HGVS p.) | p.Gln129Pro |
| Coding change (HGVS c.) | c.386A>C |
| MANE Select transcript | [NM_031431](https://www.ncbi.nlm.nih.gov/nuccore/NM_031431) |
| Variant type | single nucleotide variant |
| Location | chr13:45480127-45480127 (GRCh38) |
| ClinVar | [VCV3494951](https://www.ncbi.nlm.nih.gov/clinvar/variation/3494951/) |

**All HGVS expressions:** `NC_000013.10:g.46054262A>C`, `NC_000013.11:g.45480127A>C`, `NM_031431.4:c.386A>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.353) — no call either way
- REVEL 0.2 (benign-leaning)
- SaProt LLR -11.487 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.87) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.266, GERP 1.85, phastCons 1 — highly conserved
- CADD: **PHRED 22.2**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (45,465,037–45,491,538), spanning 26,501 bp. Chi-square p 0.75. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.87**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.012%** (afr) · FAF95 0.00624% · FAF99 0.00468% · 9/74,826 in the highest group · 9/1,608,248 alleles overall — ultra-rare (popmax 0.012%, afr).

*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}

**COG3** population constraint: LOEUF 0.314, pLI 1, missense-Z 1.8639. *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):

- **congenital disorder of glycosylation** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.82, 39% of residues very-high.

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

*Describes the biological roles of COG3 (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}

COG3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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, endoplasmic reticulum to Golgi vesicle-mediated transport, retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum, intra-Golgi vesicle-mediated transport, Golgi organization, glycoprotein biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-04 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related COG3 variant pages (same residue, condition, or type): [COG3 p.Gln129Arg](/variant/cog3-p-gln129arg), [COG3 p.Ala14Val](/variant/cog3-p-ala14val), [COG3 p.Ala190Gly](/variant/cog3-p-ala190gly), [COG3 p.Ala227Asp](/variant/cog3-p-ala227asp), [COG3 p.Ala227Thr](/variant/cog3-p-ala227thr), [COG3 p.Ala2Val](/variant/cog3-p-ala2val), [COG3 p.Ala302Gly](/variant/cog3-p-ala302gly), [COG3 p.Ala364Ser](/variant/cog3-p-ala364ser).

### 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 3494951). 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.*