Is EXT2 p.Asp227Asn (c.679G>A) pathogenic?

EXT2 p.Asp227Asn (c.679G>A) is classified Pathogenic in EXT2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-17). AlphaMissense: likely pathogenic (0.9867); Very rare (popmax 0.00134%, afr); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Asp227Asn (c.679G>A)?

EXT2 p.Asp227Asn (c.679G>A) is associated with exostoses, multiple, type 2, seizures-scoliosis-macrocephaly syndrome (ClinVar).

How common is EXT2 p.Asp227Asn (c.679G>A) in the general population?

EXT2 p.Asp227Asn (c.679G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Multiple osteochondromas inherited?

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

What do computational predictors say about EXT2 p.Asp227Asn (c.679G>A)?

AlphaMissense predicts likely pathogenic (score 0.9867) — an in-silico prediction, not a clinical call.

EXT2 p.Asp227Asn

c.679G>A · rs121918280 · VCV2474

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.9867	likely pathogenic ✓ concordant with ClinVar
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -11.47	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	33.0	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 0.00134% African / African-American · 1/74,898 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,984 alleles · very rare exomes 3/1,461,838 · genomes 2/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,898
European (non-Finnish)	0.000339%	294,997

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.Asp227Asn
Coding: c.679G>A
MANE Select: NM_207122
dbSNP: rs121918280
Type: single nucleotide variant
Location: chr11:44114237 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 227: a UniProt-annotated variant site (in ext2; no effect on oligomeric complex formation with ext1); a β-strand

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: seizures-scoliosis-macrocephaly syndrome

For Multiple osteochondromas (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: >1 / 1000 (Specific population)

Similar variants

EXT2 p.Asp227Gly Pathogenic ★ same residue
EXT2 p.Asp227Val Likely pathogenic ★ same residue
EXT2 p.Asp227Glu Uncertain significance ★ ⚠ same residue
EXT2 p.Asp227Tyr 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

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-asp227asn (accessed [today's date]).

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