# NM_015386.3(COG4):c.2006C>T (p.Ala669Val)

https://sugi.bio/variant/cog4-p-ala669val

## Summary

**COG4 p.Ala669Val (c.2006C>T)** is classified **Likely pathogenic** in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). Absent from gnomAD v4.1; Associated with microcephalic osteodysplastic dysplasia, Saul-Wilson type.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs539535604 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the COG4 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to microcephalic osteodysplastic dysplasia, Saul-Wilson type.

*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) | Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COG4 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Microcephalic osteodysplastic dysplasia, Saul-Wilson type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Very frequent (99-80%)
- Malar flattening — Very frequent (99-80%)
- Convex nasal ridge — Very frequent (99-80%)
- Narrow nasal bridge — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)
- Proptosis — Very frequent (99-80%)
- Platyspondyly — Very frequent (99-80%)
- Talipes equinovarus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016736/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COG4](https://sugi.bio/atlas/gene/COG4/) |
| Protein change (HGVS p.) | p.Ala669Val |
| Coding change (HGVS c.) | c.2006C>T |
| MANE Select transcript | [NM_015386](https://www.ncbi.nlm.nih.gov/nuccore/NM_015386) |
| dbSNP | [rs539535604](https://www.ncbi.nlm.nih.gov/snp/rs539535604/) |
| Variant type | single nucleotide variant |
| Location | chr16:70481864-70481864 (GRCh38) |
| ClinVar | [VCV3065319](https://www.ncbi.nlm.nih.gov/clinvar/variation/3065319/) |

**All HGVS expressions:** `NC_000016.10:g.70481864G>A`, `NC_000016.9:g.70515767G>A`, `NG_027529.1:g.46691C>T`, `NM_001195139.2:c.1931C>T`, `NM_001365426.1:c.1580C>T`, `NM_015386.3:c.2006C>T`, `NR_158212.1:n.1965C>T`

## 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 6.696, GERP 1.73, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.7**. 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 1.06** across the covering region of the MANE Select transcript (70,481,013–70,523,543), spanning 42,530 bp. Chi-square p 0.075. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.62 acceptor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**COG4** population constraint: LOEUF 0.805, pLI 1.9463e-13, missense-Z -0.0047756; 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):

- **microcephalic osteodysplastic dysplasia, Saul-Wilson type** — Definitive (AD)
- **COG4-congenital disorder of glycosylation** — Moderate (AR)

## Protein context {#protein}

Residue **669** lies in an α-helix; the 'd domain' region.

AlphaFold model confidence (whole protein): pLDDT 85.29, 50% of residues very-high.

**1 experimental structure(s)** (PDB): [3HR0](https://www.rcsb.org/structure/3HR0).

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

*Describes the biological roles of COG4 (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:** COG4's established molecular role includes identical protein binding. p.Ala669Val falls in the d domain region.


### Pathways affected {#pathways}

COG4 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}

**Molecular function:** identical protein binding.

**Biological process:** retrograde transport, vesicle recycling within Golgi, retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum, Golgi organization.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-26 |

## Associated conditions {#conditions}

[microcephalic osteodysplastic dysplasia, Saul-Wilson type](https://sugi.bio/atlas/disease/microcephalic-osteodysplastic-dysplasia-saul-wilson-type/).

**Reported phenotype names (ClinVar):** Microcephalic osteodysplastic dysplasia, Saul-Wilson type, MICROCEPHALIC OSTEODYSPLASTIC DYSPLASIA, Saul-Wilson Syndrome.

## Same-residue context {#hotspot}

Residue **669** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [COG4 p.Ala669Pro](/variant/cog4-p-ala669pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related COG4 variant pages (same residue, condition, or type): [COG4 p.Ala669Pro](/variant/cog4-p-ala669pro), [COG4 p.Glu614Ter](/variant/cog4-p-glu614ter), [COG4 p.Gly25Ter](/variant/cog4-p-gly25ter), [COG4 p.Gly516Arg](/variant/cog4-p-gly516arg), [COG4 p.Ala544Val](/variant/cog4-p-ala544val), [COG4 p.Pro12Leu](/variant/cog4-p-pro12leu), [COG4 p.Thr699Ala](/variant/cog4-p-thr699ala), [COG4 c.1482-25T>C](/variant/cog4-c-1482-minus-25t-c).

### 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 3065319). 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.*