# NM_006302.3(MOGS):c.2017G>A (p.Val673Ile)

https://sugi.bio/variant/mogs-p-val673ile

## Summary

**MOGS p.Val673Ile (c.2017G>A)** is classified **Benign/Likely benign** in MOGS (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0773); Low-frequency (popmax 2.28%, mid); Associated with MOGS-congenital disorder of glycosylation.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs114933392 · 9 submitters · 1 linked condition · AlphaMissense likely benign · low-frequency (popmax 2.28%, mid)

## For patients & families {#patients}

This is a change in the MOGS gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters, and is linked to MOGS-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) | Infancy, Neonatal |
| Diagnostic panels | MOGS is a diagnostic-grade gene on 14 Genomics England panels |

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

- Retrognathia — Frequent (79-30%)
- Wide nose — Frequent (79-30%)
- Long eyelashes — Frequent (79-30%)
- Hirsutism — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Abnormal facial shape — Frequent (79-30%)
- Decreased circulating IgA level — Frequent (79-30%)
- Decreased circulating total IgM — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010767/index) · [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.Val673Ile |
| Coding change (HGVS c.) | c.2017G>A |
| MANE Select transcript | [NM_006302](https://www.ncbi.nlm.nih.gov/nuccore/NM_006302) |
| dbSNP | [rs114933392](https://www.ncbi.nlm.nih.gov/snp/rs114933392/) |
| Variant type | single nucleotide variant |
| Location | chr2:74461772-74461772 (GRCh38) |
| ClinVar | [VCV218681](https://www.ncbi.nlm.nih.gov/clinvar/variation/218681/) |

**All HGVS expressions:** `LRG_1226:g.8639G>A`, `LRG_1226t1:c.2017G>A`, `NC_000002.11:g.74688899C>T`, `NC_000002.12:g.74461772C>T`, `NG_008922.1:g.8639G>A`, `NM_001146158.2:c.1699G>A`, `NM_006302.3:c.2017G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0773)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.249 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.596, GERP -2.04, phastCons 0.1 — weakly conserved position
- CADD: **PHRED 12.7**. 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 1.03** across the covering region of the MANE Select transcript (74,461,278–74,461,879), spanning 601 bp. Chi-square p 0.59. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **2.28%** (mid) · FAF95 1.97% · FAF99 1.85% · 138/6,062 in the highest group · 17,442/1,614,216 alleles overall — low-frequency (popmax 2.28%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 3.47% | 29 |
| Ashkenazi Jewish (not grpmax-eligible) | 2.34% | 43 |
| Middle Eastern (grpmax) | 2.28% | 44 |
| Remaining individuals (not grpmax-eligible) | 1.1% | 91 |
| European (non-Finnish) | 1.08% | 92 |
| South Asian | 0.609% | 164 |
| Admixed American | 0.361% | 277 |
| African / African-American | 0.203% | 494 |
| East Asian | 0.00223% | 44,890 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (8 Benign, 1 Likely benign).

**Submission history:** 9 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2024-09-13 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-05-09 |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Benign | criteria provided, single submitter | clinical testing | 2015-02-19 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-06-01 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-11 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** MOGS-congenital disorder of glycosylation, not specified, not provided, none provided, AllHighlyPenetrant, CDG IIb, GLUCOSIDASE I DEFICIENCY, CDG 2B, MOGS-CDG.

## Similar variants {#similar}

Related MOGS variant pages (same residue, condition, or type): [MOGS p.Val673Ala](/variant/mogs-p-val673ala), [MOGS p.Arg495Ter](/variant/mogs-p-arg495ter), [MOGS p.Gln124Ter](/variant/mogs-p-gln124ter), [MOGS p.Gln505Ter](/variant/mogs-p-gln505ter), [MOGS p.Ala22Glu](/variant/mogs-p-ala22glu), [MOGS p.Ala292Asp](/variant/mogs-p-ala292asp), [MOGS p.Ala292Pro](/variant/mogs-p-ala292pro), [MOGS p.Ala41Val](/variant/mogs-p-ala41val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 218681). 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.*