Is GNE p.His558= (c.1674C>T) pathogenic?

GNE p.His558= (c.1674C>T) is classified Conflicting classifications of pathogenicity in GNE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.0329%, mid); Associated with sialuria.

What condition is associated with GNE p.His558= (c.1674C>T)?

GNE p.His558= (c.1674C>T) is associated with sialuria, GNE myopathy (ClinVar).

How common is GNE p.His558= (c.1674C>T) in the general population?

GNE p.His558= (c.1674C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Sialuria inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

GNE p.His558=

c.1674C>T · rs144931111 · VCV499816

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

sialuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.1	GERP -3.4
Overall
CADD	0.534	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,074 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00105% 17/1,613,978 alleles · ultra-rare exomes 14/1,461,822 · genomes 3/152,156 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,037
African / African-American	0.00935%	10,699
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,086
European (non-Finnish)	0.000339%	294,996

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GNE
Protein: p.His558=
Coding: c.1674C>T
MANE Select: NM_005476
dbSNP: rs144931111
Type: single nucleotide variant
Location: chr9:36219980 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.96 · 5 PDB
Residue 558: the 'n-acetylmannosamine kinase' region; a UniProt-annotated variant site (in thc12; likely pathogenic)

Full GNE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sialuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: GNE myopathy

For Sialuria (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy

Similar variants

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GNE c.617-1G>A Likely pathogenic ★★ same condition
GNE c.617-2A>G Pathogenic/Likely pathogenic ★★ same condition
GNE c.982+2T>A Likely pathogenic ★★ same condition
GNE p.Ala524Val Pathogenic/Likely pathogenic ★★ same condition
GNE p.Ala630Thr Pathogenic/Likely pathogenic ★★ same condition
GNE p.Ala631Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gne-p-his558 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown