# NM_006302.3(MOGS):c.646del (p.Val216fs)

https://sugi.bio/variant/mogs-p-val216fs

## Summary

**MOGS p.Val216fs (c.646del)** is classified **Pathogenic/Likely pathogenic** in MOGS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-14). Very rare (popmax 0.004%, afr); Associated with MOGS-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs777654978 · 3 submitters · 2 linked conditions · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the MOGS gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to MOGS-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 | [MOGS](https://sugi.bio/atlas/gene/MOGS/) |
| Protein change (HGVS p.) | p.Val216fs |
| Coding change (HGVS c.) | c.646del |
| MANE Select transcript | [NM_006302](https://www.ncbi.nlm.nih.gov/nuccore/NM_006302) |
| dbSNP | [rs777654978](https://www.ncbi.nlm.nih.gov/snp/rs777654978/) |
| Variant type | Deletion |
| Location | chr2:74463320-74463320 (GRCh38) |
| ClinVar | [VCV565387](https://www.ncbi.nlm.nih.gov/clinvar/variation/565387/) |

**All HGVS expressions:** `LRG_1226:g.7091del`, `LRG_1226t1:c.646del`, `NC_000002.11:g.74690447del`, `NC_000002.12:g.74463320del`, `NG_008922.1:g.7091del`, `NM_001146158.2:c.328del`, `NM_006302.3:c.646del`

## 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 2.21, GERP 1.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.85, pLI 2.6946e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 4**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 29.2**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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 **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,932 in the highest group · 6/1,614,098 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.004% | 24,977 |
| European (non-Finnish) | 0.000254% | 393,351 |

*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}

**MOGS** population constraint: LOEUF 0.85, pLI 2.6946e-10, missense-Z 0.86484. *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):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.42, 86% of residues very-high.

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

*Describes the biological roles of MOGS (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:** MOGS participates in disease-associated pathways. In Reactome, MOGS is annotated in disease pathway(s) including **Defective MOGS causes CDG-2b**, **Maturation of spike protein**.

**Disease mechanism (Reactome):** MOGS loss or alteration is curated in [Defective MOGS causes CDG-2b](https://reactome.org/content/detail/R-HSA-4793954), [Maturation of spike protein](https://reactome.org/content/detail/R-HSA-9683686), [Maturation of spike protein](https://reactome.org/content/detail/R-HSA-9694548).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective MOGS causes CDG-2b](https://reactome.org/content/detail/R-HSA-4793954) | curated |
| ⚕ [Maturation of spike protein](https://reactome.org/content/detail/R-HSA-9683686) | curated |
| ⚕ [Maturation of spike protein](https://reactome.org/content/detail/R-HSA-9694548) | curated |
| [N-glycan trimming in the ER and Calnexin/Calreticulin cycle](https://reactome.org/content/detail/R-HSA-532668) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-07-14.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2021–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-28 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-07-14 |

## Associated conditions {#conditions}

[MOGS-related disorder](https://sugi.bio/atlas/disease/mogs-related-disorder/), [MOGS-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/mogs-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** MOGS-related disorder, MOGS-congenital disorder of glycosylation, MOGS-related condition, CDG IIb, GLUCOSIDASE I DEFICIENCY, MOGS-CDG, CDG 2B.

## Similar variants {#similar}

Related MOGS variant pages (same residue, condition, or type): [MOGS p.Glu295fs](/variant/mogs-p-glu295fs), [MOGS p.Asp141fs](/variant/mogs-p-asp141fs), [MOGS p.Asp212fs](/variant/mogs-p-asp212fs), [MOGS p.Gln408fs](/variant/mogs-p-gln408fs), [MOGS p.His151fs](/variant/mogs-p-his151fs), [MOGS p.Ile402fs](/variant/mogs-p-ile402fs), [MOGS p.Lys278fs](/variant/mogs-p-lys278fs), [MOGS p.Pro294fs](/variant/mogs-p-pro294fs).

### 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 565387). 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.*