Is EXT2 p.Ser347Cys (c.1040C>G) pathogenic?

EXT2 p.Ser347Cys (c.1040C>G) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-21). AlphaMissense: ambiguous (0.352); Ultra-rare (popmax 0.0156%, eas); Associated with seizures-scoliosis-macrocephaly syndrome.

What condition is associated with EXT2 p.Ser347Cys (c.1040C>G)?

EXT2 p.Ser347Cys (c.1040C>G) is associated with seizures-scoliosis-macrocephaly syndrome, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Ser347Cys (c.1040C>G) in the general population?

EXT2 p.Ser347Cys (c.1040C>G) is ultra-rare (popmax 0.0156%, eas) (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.Ser347Cys (c.1040C>G)?

AlphaMissense predicts ambiguous (score 0.352) — an in-silico prediction, not a clinical call.

EXT2 p.Ser347Cys

c.1040C>G · rs746031826 · VCV2910977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.352 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

seizures-scoliosis-macrocephaly syndrome

Computational evidence

Protein change
AlphaMissense	0.352	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -12.88	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	27.6	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 0.0156% East Asian · 7/44,884 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000805% 13/1,614,008 alleles · ultra-rare exomes 8/1,461,890 · genomes 5/152,118 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
African / African-American	0.00668%	14,980
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ser347Cys
Coding: c.1040C>G
MANE Select: NM_207122
dbSNP: rs746031826
Type: single nucleotide variant
Location: chr11:44126916 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB

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 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
EXT2 c.626+1G>T 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/ext2-p-ser347cys (accessed [today's date]).

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