# NM_005476.7(GNE):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/gne-p-arg306gln

## Summary

**GNE p.Arg306Gln (c.917G>A)** is classified **Likely pathogenic** in GNE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-17). AlphaMissense: likely pathogenic (0.9642); Very rare (popmax 0.00223%, eas); Associated with sialuria.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1455785164 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the GNE gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to sialuria.

*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 dominant |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | GNE is a diagnostic-grade gene on 11 Genomics England panels |

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

- Thin upper lip vermilion — Very frequent (99-80%)
- Coarse facial features — Very frequent (99-80%)
- Epicanthus — Very frequent (99-80%)
- Hypertelorism — Very frequent (99-80%)
- Smooth philtrum — Very frequent (99-80%)
- Low-set ears — Very frequent (99-80%)
- Wide nasal bridge — Very frequent (99-80%)
- Periorbital fullness — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004865/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GNE](https://sugi.bio/atlas/gene/GNE/) |
| Protein change (HGVS p.) | p.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_005476](https://www.ncbi.nlm.nih.gov/nuccore/NM_005476) |
| dbSNP | [rs1455785164](https://www.ncbi.nlm.nih.gov/snp/rs1455785164/) |
| Variant type | single nucleotide variant |
| Location | chr9:36233985-36233985 (GRCh38) |
| ClinVar | [VCV498574](https://www.ncbi.nlm.nih.gov/clinvar/variation/498574/) |

**All HGVS expressions:** `LRG_1197:g.48060G>A`, `LRG_1197t1:c.1010G>A`, `LRG_1197t2:c.917G>A`, `NC_000009.11:g.36233982C>T`, `NC_000009.12:g.36233985C>T`, `NG_008246.1:g.48060G>A`, `NM_001128227.3:c.1010G>A`, `NM_001190383.3:c.917G>A`, `NM_001190384.3:c.587G>A`, `NM_001190388.2:c.740G>A`, `NM_001374797.1:c.764G>A`, `NM_001374798.1:c.740G>A`, `NM_005476.7:c.917G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9642) — concordant with the pathogenic call
- REVEL 0.872 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.481 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.621, GERP 1.53, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.67** across the covering region of the MANE Select transcript (36,217,368–36,249,355), spanning 31,987 bp. Chi-square p 1.8e-23. 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 **0.00223%** (eas) · 1/44,884 in the highest group · 3/1,614,204 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,884 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,040 |
| European (non-Finnish) | 8.47e-05% | 1,180,026 |

*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}

**GNE** population constraint: LOEUF 0.821, pLI 1.6876e-06, missense-Z 4.0011. *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):

- **macrothrombocytopenia, isolated** — Definitive (AR)

## Protein context {#protein}

Residue **306** lies in an α-helix; a UniProt-annotated variant site (in nm).

AlphaFold model confidence (whole protein): pLDDT 92.96, 88% of residues very-high.

**5 experimental structure(s)** (PDB): [2YHW](https://www.rcsb.org/structure/2YHW), [2YHY](https://www.rcsb.org/structure/2YHY), [2YI1](https://www.rcsb.org/structure/2YI1), [3EO3](https://www.rcsb.org/structure/3EO3), [4ZHT](https://www.rcsb.org/structure/4ZHT).

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

*Describes the biological roles of GNE (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:** GNE's established molecular role includes UDP-N-acetylglucosamine 2-epimerase activity. In Reactome, GNE is annotated in disease pathway(s) including **Defective GNE causes sialuria, NK and IBM2**.

**Disease mechanism (Reactome):** GNE loss or alteration is curated in [Defective GNE causes sialuria, NK and IBM2](https://reactome.org/content/detail/R-HSA-4085011).

### Pathways affected {#pathways}

GNE participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective GNE causes sialuria, NK and IBM2](https://reactome.org/content/detail/R-HSA-4085011) | curated |
| [Sialic acid metabolism](https://reactome.org/content/detail/R-HSA-4085001) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** UDP-N-acetylglucosamine 2-epimerase activity, N-acylmannosamine kinase activity.

**Biological process:** CMP-N-acetylneuraminate biosynthetic process, N-acetylneuraminate biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-17.

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

**Submission history:** 3 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | flagged submission | clinical testing | 2016-11-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-12 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-17 |

## Associated conditions {#conditions}

[sialuria](https://sugi.bio/atlas/disease/sialuria/), [GNE myopathy](https://sugi.bio/atlas/disease/gne-myopathy/), [thrombocytopenia 12 with or without myopathy](https://sugi.bio/atlas/disease/thrombocytopenia-12-with-or-without-myopathy/).

**Reported phenotype names (ClinVar):** Sialuria, not provided, GNE myopathy, Thrombocytopenia 12 with or without myopathy, none provided, Sialic Acid Storage Disease, SIALURIA, FRENCH TYPE, NONAKA DISTAL MYOPATHY, MYOPATHY, DISTAL, WITH OR WITHOUT RIMMED VACUOLES, INCLUSION BODY MYOPATHY, HEREDITARY, AUTOSOMAL RECESSIVE.

## Same-residue context {#hotspot}

Residue **306** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GNE p.Arg306Ter](/variant/gne-p-arg306ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GNE variant pages (same residue, condition, or type): [GNE p.Arg306Ter](/variant/gne-p-arg306ter), [GNE c.1816+2T>C](/variant/gne-c-1816-plus-2t-c), [GNE c.1816+5G>A](/variant/gne-c-1816-plus-5g-a), [GNE c.617-1G>A](/variant/gne-c-617-minus-1g-a), [GNE c.617-2A>G](/variant/gne-c-617-minus-2a-g), [GNE c.982+2T>A](/variant/gne-c-982-plus-2t-a), [GNE p.Ala524Val](/variant/gne-p-ala524val), [GNE p.Ala630Thr](/variant/gne-p-ala630thr).

### 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 498574). 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.*