Is EXT2 p.Leu486= (c.1458T>A) pathogenic?

EXT2 p.Leu486= (c.1458T>A) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-24). Very rare (popmax 0.00322%, nfe); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Leu486= (c.1458T>A)?

EXT2 p.Leu486= (c.1458T>A) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Leu486= (c.1458T>A) in the general population?

EXT2 p.Leu486= (c.1458T>A) is very rare (popmax 0.00322%, nfe) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT2 p.Leu486=

c.1458T>A · rs1343630556 · VCV879983

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Conditions

exostoses, multiple, type 2

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 -1.9	GERP -3.2
Overall
CADD	0.507	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00322% European (non-Finnish) · 38/1,179,978 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00248% 40/1,614,080 alleles · very rare exomes 40/1,461,796 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,052
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,028

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.Leu486=
Coding: c.1458T>A
MANE Select: NM_207122
dbSNP: rs1343630556
Type: single nucleotide variant
Location: chr11:44197981 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 486: 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

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT2 p.Leu486His 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-leu486 (accessed [today's date]).

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