Is EXT2 p.Met87Arg (c.260T>G) pathogenic?

EXT2 p.Met87Arg (c.260T>G) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.8454); Ultra-rare (popmax 0.0466%, amr); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Met87Arg (c.260T>G)?

EXT2 p.Met87Arg (c.260T>G) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Met87Arg (c.260T>G) in the general population?

EXT2 p.Met87Arg (c.260T>G) is ultra-rare (popmax 0.0466%, amr) (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.Met87Arg (c.260T>G)?

AlphaMissense predicts likely pathogenic (score 0.8454) — an in-silico prediction, not a clinical call.

EXT2 p.Met87Arg

c.260T>G · rs140075817 · VCV134211

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8454 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0466%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.8454	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	24.7	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 0.0466% Admixed American · 28/60,028 alleles

Filtering AF 0.0364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0324% 523/1,614,200 alleles · ultra-rare exomes 477/1,461,868 · genomes 46/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0466%	2,144
European (non-Finnish)	0.0393%	2,543
Remaining individualsnot grpmax-eligible	0.0368%	2,718
African / African-American	0.00666%	15,012
Finnishnot grpmax-eligible	0.00468%	21,347

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.Met87Arg
Coding: c.260T>G
MANE Select: NM_207122
dbSNP: rs140075817
Type: single nucleotide variant
Location: chr11:44107972 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 87: a UniProt-annotated variant site (in ssms; decreased protein abundance; levels of the ext2-interacting protein ndst1 are abolished in patient cells); an α-helix

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.Met87Ile 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-met87arg (accessed [today's date]).

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