Is EXT2 p.Arg557Trp (c.1669C>T) pathogenic?

EXT2 p.Arg557Trp (c.1669C>T) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-07). AlphaMissense: likely pathogenic (0.9604); Very rare (popmax 0.00788%, nfe); Associated with seizures-scoliosis-macrocephaly syndrome.

What condition is associated with EXT2 p.Arg557Trp (c.1669C>T)?

EXT2 p.Arg557Trp (c.1669C>T) is associated with seizures-scoliosis-macrocephaly syndrome, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg557Trp (c.1669C>T) in the general population?

EXT2 p.Arg557Trp (c.1669C>T) is very rare (popmax 0.00788%, nfe) (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.Arg557Trp (c.1669C>T)?

AlphaMissense predicts likely pathogenic (score 0.9604) — an in-silico prediction, not a clinical call.

EXT2 p.Arg557Trp

c.1669C>T · rs768532662 · VCV1421787

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

seizures-scoliosis-macrocephaly syndrome

Computational evidence

Protein change
AlphaMissense	0.9604	likely pathogenic
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -14.92	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 -0.023	GERP 0.28, phastCons 0.73
Regional constraint	o/e 0.62	unconstrained · MANE · 37 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	27.7	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 0.00788% European (non-Finnish) · 93/1,179,880 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00682% 110/1,613,696 alleles · very rare exomes 108/1,461,620 · genomes 2/152,076 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0224%	4,462
European (non-Finnish)grpmax	0.00788%	12,687
East Asian	0.00668%	14,963

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg557Trp
Coding: c.1669C>T
MANE Select: NM_207122
dbSNP: rs768532662
Type: single nucleotide variant
Location: chr11:44232359 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 557: 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.Arg557= 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
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-arg557trp (accessed [today's date]).

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