Is EXT2 p.Met1del (c.-1_2del) pathogenic?

EXT2 p.Met1del (c.-12del) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). Very rare (popmax 0.000248%); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Met1del (c.-1_2del)?

EXT2 p.Met1del (c.-1_2del) is associated with exostoses, multiple, type 2, seizures-scoliosis-macrocephaly syndrome (ClinVar).

How common is EXT2 p.Met1del (c.-1_2del) in the general population?

EXT2 p.Met1del (c.-1_2del) is very rare (popmax 0.000248%) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT2 p.Met1del

c.-1_2del · VCV3599598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000248%)

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP 2.3, phastCons 1
Overall
CADD	16.47	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000248%

Overall 0.000248% 4/1,613,788 alleles · very rare exomes 2/1,461,586 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,339
Remaining individualsnot grpmax-eligible	0.0016%	62,472

Finnish 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.Met1del
Coding: c.-1_2del
MANE Select: NM_207122
Type: Deletion
Location: chr11:44107710 (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

Also linked: seizures-scoliosis-macrocephaly syndrome

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT2 c.626+2_626+5del Pathogenic ★★ same condition
EXT2 p.Gln382fs Pathogenic ★★ same condition
EXT2 p.Val593fs Likely pathogenic ★★ same condition
EXT2 p.Val68fs Pathogenic ★★ same condition
EXT2 c.2019-2del Uncertain significance ★★ same condition
EXT2 c.1806+9del Benign/Likely benign ★★ same condition
EXT2 c.1080-2del Pathogenic ★ same condition
EXT2 c.1489_1495+12del 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-met1del (accessed [today's date]).

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