Is EXT2 p.Arg250Trp (c.748C>T) pathogenic?

EXT2 p.Arg250Trp (c.748C>T) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: ambiguous (0.4211); Ultra-rare (popmax 0.0178%, eas); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Arg250Trp (c.748C>T)?

EXT2 p.Arg250Trp (c.748C>T) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg250Trp (c.748C>T) in the general population?

EXT2 p.Arg250Trp (c.748C>T) is ultra-rare (popmax 0.0178%, eas) (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.Arg250Trp (c.748C>T)?

AlphaMissense predicts ambiguous (score 0.4211) — an in-silico prediction, not a clinical call.

EXT2 p.Arg250Trp

c.748C>T · rs183424469 · VCV1047236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4211 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.4211	ambiguous
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -15.38	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 3.4	GERP -0.23, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	27.0	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 0.0178% East Asian · 8/44,876 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00427% 69/1,614,038 alleles · ultra-rare exomes 63/1,461,796 · genomes 6/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
Middle Eastern	0.0165%	6,062
South Asian	0.00988%	10,119
Finnishnot grpmax-eligible	0.00781%	12,802
Remaining individualsnot grpmax-eligible	0.0064%	15,624
African / African-American	0.004%	25,009
European (non-Finnish)	0.00331%	30,255

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.Arg250Trp
Coding: c.748C>T
MANE Select: NM_207122
dbSNP: rs183424469
Type: single nucleotide variant
Location: chr11:44124793 (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

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

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT2 p.Arg250Gln 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-arg250trp (accessed [today's date]).

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