Is EXT2 p.Arg223Trp (c.667C>T) pathogenic?

EXT2 p.Arg223Trp (c.667C>T) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-19). AlphaMissense: likely pathogenic (0.9848); Ultra-rare (popmax 0.0165%, mid); Associated with seizures-scoliosis-macrocephaly syndrome.

What condition is associated with EXT2 p.Arg223Trp (c.667C>T)?

EXT2 p.Arg223Trp (c.667C>T) is associated with seizures-scoliosis-macrocephaly syndrome, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg223Trp (c.667C>T) in the general population?

EXT2 p.Arg223Trp (c.667C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg223Trp (c.667C>T)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

EXT2 p.Arg223Trp

c.667C>T · rs201062014 · VCV1441831

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

seizures-scoliosis-macrocephaly syndrome

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00149% 24/1,614,098 alleles · ultra-rare exomes 21/1,461,832 · genomes 3/152,266 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00223%	44,882
South Asian	0.0022%	45,544
European (non-Finnish)	0.00136%	73,749
African / African-American	0.00133%	75,026

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.Arg223Trp
Coding: c.667C>T
MANE Select: NM_207122
dbSNP: rs201062014
Type: single nucleotide variant
Location: chr11:44114225 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 223: a UniProt-annotated variant site (in ext2)

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.Arg223Gln Uncertain significance ★★ ⚠ same residue
EXT2 p.Arg223Pro Pathogenic ★ same residue
EXT2 p.Arg223= Likely benign ★ 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

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-arg223trp (accessed [today's date]).

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