Is EXT2 p.Arg393Gln (c.1178G>A) pathogenic?

EXT2 p.Arg393Gln (c.1178G>A) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0779); Rare (popmax 0.238%, amr); Associated with seizures-scoliosis-macrocephaly syndrome.

What condition is associated with EXT2 p.Arg393Gln (c.1178G>A)?

EXT2 p.Arg393Gln (c.1178G>A) is associated with seizures-scoliosis-macrocephaly syndrome, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg393Gln (c.1178G>A) in the general population?

EXT2 p.Arg393Gln (c.1178G>A) is rare (popmax 0.238%, amr) (gnomAD).

How is Seizures-scoliosis-macrocephaly syndrome inherited?

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

What do computational predictors say about EXT2 p.Arg393Gln (c.1178G>A)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

EXT2 p.Arg393Gln

c.1178G>A · rs138187791 · VCV134218

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.238%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

seizures-scoliosis-macrocephaly syndrome

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.483	indeterminate
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.238% Admixed American · 143/60,024 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.194%

Overall 0.151% 2,441/1,614,128 alleles · rare exomes 2,273/1,461,870 · genomes 168/152,258 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.238%	420
European (non-Finnish)	0.184%	542
Remaining individualsnot grpmax-eligible	0.131%	762
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
African / African-American	0.0227%	4,414
Middle Eastern	0.0165%	6,062
South Asian	0.0132%	7,590
Finnishnot grpmax-eligible	0.00469%	21,339

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.Arg393Gln
Coding: c.1178G>A
MANE Select: NM_207122
dbSNP: rs138187791
Type: single nucleotide variant
Location: chr11:44171615 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 393: 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

Also linked: exostoses, multiple, type 2

For Seizures-scoliosis-macrocephaly syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

EXT2 p.Arg393Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
EXT2 c.1079+1G>A Pathogenic ★★ same condition
EXT2 c.1079+1G>T Pathogenic ★★ same condition
EXT2 c.1173+1G>A Pathogenic ★★ same condition
EXT2 c.1662+1G>C Likely pathogenic ★★ same condition
EXT2 c.536+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>C 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-arg393gln (accessed [today's date]).

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