Is EXT2 p.Asp333= (c.999T>C) pathogenic?

EXT2 p.Asp333= (c.999T>C) is classified Benign/Likely benign in EXT2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). Low-frequency (popmax 4.03%, afr); Associated with exostoses, multiple, type 1.

What condition is associated with EXT2 p.Asp333= (c.999T>C)?

EXT2 p.Asp333= (c.999T>C) is associated with exostoses, multiple, type 1, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Asp333= (c.999T>C) in the general population?

EXT2 p.Asp333= (c.999T>C) is low-frequency (popmax 4.03%, afr) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT2 p.Asp333=

c.999T>C · rs61733300 · VCV304584

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.03%, afr)

Conditions

exostoses, multiple, type 1

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 -6	GERP -5.2
Overall
CADD	0.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.03% African / African-American · 3,024/75,032 alleles

Filtering AF 3.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.86%

Overall 0.311% 5,014/1,614,210 alleles · low-frequency exomes 3,195/1,461,888 · genomes 1,819/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.03%	25
South Asian	1.07%	94
East Asian	0.53%	189
Remaining individualsnot grpmax-eligible	0.491%	204
Middle Eastern	0.363%	276
Admixed American	0.291%	343
Ashkenazi Jewishnot grpmax-eligible	0.27%	370
European (non-Finnish)	0.0162%	6,178
Finnishnot grpmax-eligible	0.00468%	21,348

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.Asp333=
Coding: c.999T>C
MANE Select: NM_207122
dbSNP: rs61733300
Type: single nucleotide variant
Location: chr11:44126875 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 333: an α-helix

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

Disease context

exostoses, multiple, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 2

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT2 p.Asp333Asn 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
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-asp333 (accessed [today's date]).

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