Is EXT2 p.Cys339= (c.1017T>C) pathogenic?

EXT2 p.Cys339= (c.1017T>C) is classified Benign/Likely benign in EXT2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.89%, afr); Associated with seizures-scoliosis-macrocephaly syndrome.

What condition is associated with EXT2 p.Cys339= (c.1017T>C)?

EXT2 p.Cys339= (c.1017T>C) is associated with seizures-scoliosis-macrocephaly syndrome, exostoses, multiple, type 1, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Cys339= (c.1017T>C) in the general population?

EXT2 p.Cys339= (c.1017T>C) is low-frequency (popmax 2.89%, afr) (gnomAD).

How is Seizures-scoliosis-macrocephaly syndrome inherited?

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

EXT2 p.Cys339=

c.1017T>C · rs11828047 · VCV304585

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, afr)

Conditions

seizures-scoliosis-macrocephaly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -5.2
Overall
CADD	6.041	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.89% African / African-American · 2,171/75,056 alleles

Filtering AF 2.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.75%

Overall 0.162% 2,614/1,614,210 alleles · low-frequency exomes 1,297/1,461,888 · genomes 1,317/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.89%	35
Admixed American	0.3%	334
Remaining individualsnot grpmax-eligible	0.248%	403
Middle Eastern	0.248%	404
South Asian	0.00988%	10,119
European (non-Finnish)	0.00712%	14,048

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.Cys339=
Coding: c.1017T>C
MANE Select: NM_207122
dbSNP: rs11828047
Type: single nucleotide variant
Location: chr11:44126893 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 339: a disulfide bond

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 1 exostoses, multiple, type 2

For Seizures-scoliosis-macrocephaly syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

EXT2 p.Cys339Tyr Pathogenic/Likely pathogenic ★★ same residue
EXT2 p.Cys339Ser Uncertain significance ★★ ⚠ 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

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-cys339 (accessed [today's date]).

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