Is EXT2 p.Gln391= (c.1173G>A) pathogenic?

EXT2 p.Gln391= (c.1173G>A) is classified Likely pathogenic in EXT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-06-21). Very rare (popmax 0.00333%, amr); Associated with seizures-scoliosis-macrocephaly syndrome.

What condition is associated with EXT2 p.Gln391= (c.1173G>A)?

EXT2 p.Gln391= (c.1173G>A) is associated with seizures-scoliosis-macrocephaly syndrome (ClinVar).

How common is EXT2 p.Gln391= (c.1173G>A) in the general population?

EXT2 p.Gln391= (c.1173G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Seizures-scoliosis-macrocephaly syndrome inherited?

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

EXT2 p.Gln391=

c.1173G>A · rs1457613214 · VCV816885

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

seizures-scoliosis-macrocephaly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	donor loss · deltas
Constraint at this position
Conservation	phyloP 12	phastCons 1
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,466 alleles · very rare exomes 2/1,461,200 · genomes 0/152,266 · joint denominator

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: EXT2
Protein: p.Gln391=
Coding: c.1173G>A
MANE Select: NM_207122
dbSNP: rs1457613214
Type: single nucleotide variant
Location: chr11:44130138 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 391: an α-helix

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

seizures-scoliosis-macrocephaly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Seizures-scoliosis-macrocephaly syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

EXT2 p.Gln391Glu Uncertain significance ★ ⚠ same residue
EXT2 p.Gln391Lys Likely pathogenic ★★ same residue
EXT2 p.Gln391Ter Pathogenic ★★ same residue
EXT2 c.940-2A>T Pathogenic/Likely pathogenic ★★ same condition
EXT2 p.Arg182Ter Pathogenic ★★ same condition
EXT2 p.Arg23Ter Pathogenic ★★ same condition
EXT2 p.Arg649Ter Pathogenic/Likely pathogenic ★★ same condition
EXT2 p.Asp227Asn 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/ext2-p-gln391 (accessed [today's date]).

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