# NM_006348.5(COG5):c.1410dup (p.Pro471fs)

https://sugi.bio/variant/cog5-p-pro471fs

## Summary

**COG5 p.Pro471fs (c.1410dup)** is classified **Pathogenic** in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). Ultra-rare (popmax 0.0165%, mid); Associated with COG5-congenital disorder of glycosylation.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2536102929 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the COG5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to COG5-congenital disorder of glycosylation.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | COG5 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of COG5-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Delayed speech and language development — Very frequent (99-80%)
- Motor delay — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Posteriorly rotated ears — Frequent (79-30%)
- Low-set ears — Frequent (79-30%)
- Prominent nose — Frequent (79-30%)
- Short stature — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012348/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COG5](https://sugi.bio/atlas/gene/COG5/) |
| Protein change (HGVS p.) | p.Pro471fs |
| Coding change (HGVS c.) | c.1410dup |
| MANE Select transcript | [NM_006348](https://www.ncbi.nlm.nih.gov/nuccore/NM_006348) |
| dbSNP | [rs2536102929](https://www.ncbi.nlm.nih.gov/snp/rs2536102929/) |
| Variant type | Duplication |
| Location | chr7:107283635-107283636 (GRCh38) |
| ClinVar | [VCV2014849](https://www.ncbi.nlm.nih.gov/clinvar/variation/2014849/) |

**All HGVS expressions:** `NC_000007.13:g.106924085dup`, `NC_000007.14:g.107283640dup`, `NG_028095.2:g.285879dup`, `NM_001161520.2:c.1410dup`, `NM_001379511.1:c.1314-2237dup`, `NM_001379512.1:c.1410dup`, `NM_001379513.1:c.1410dup`, `NM_001379514.1:c.1410dup`, `NM_001379515.1:c.840dup`, `NM_001379516.1:c.696dup`, `NM_006348.5:c.1410dup`, `NM_181733.4:c.1410dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.753, GERP 2.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.026, pLI 4.6848e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000429% · FAF99 0.000313% · 1/6,060 in the highest group · 11/1,461,656 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| European (non-Finnish) | 0.000848% | 117,986 |

*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}

**COG5** population constraint: LOEUF 1.026, pLI 4.6848e-17, missense-Z -0.53705. *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):

- **COG5-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.37, 64% of residues very-high.

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

*Describes the biological roles of COG5 (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}

COG5 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, Golgi organization, inter-Golgi cisterna vesicle-mediated transport.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-11 |

## Associated conditions {#conditions}

[COG5-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/cog5-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** COG5-congenital disorder of glycosylation, CDG IIi, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIi, COG5-CDG.

## Similar variants {#similar}

Related COG5 variant pages (same residue, condition, or type): [COG5 p.Pro471Leu](/variant/cog5-p-pro471leu), [COG5 p.Gly474fs](/variant/cog5-p-gly474fs), [COG5 c.1750-3dup](/variant/cog5-c-1750-minus-3dup), [COG5 c.538+6dup](/variant/cog5-c-538-plus-6dup), [COG5 p.Ser746fs](/variant/cog5-p-ser746fs), [COG5 p.Thr244fs](/variant/cog5-p-thr244fs), [COG5 p.Lys808fs](/variant/cog5-p-lys808fs), [COG5 p.Pro471Thr](/variant/cog5-p-pro471thr).

### 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 2014849). 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.*