Is EXT2 p.His303fs (c.906_907dup) pathogenic?

EXT2 p.His303fs (c.906907dup) is classified Pathogenic in EXT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-23). Very rare (popmax 0.00333%, amr); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.His303fs (c.906_907dup)?

EXT2 p.His303fs (c.906_907dup) is associated with exostoses, multiple, type 2, seizures-scoliosis-macrocephaly syndrome (ClinVar).

How common is EXT2 p.His303fs (c.906_907dup) in the general population?

EXT2 p.His303fs (c.906_907dup) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT2 p.His303fs

c.906_907dup · rs886041199 · VCV279805

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 5 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP -0.64, phastCons 0.96

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,034 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,624 alleles · very rare exomes 2/1,461,308 · genomes 0/152,316 · joint denominator

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.His303fs
Coding: c.906_907dup
MANE Select: NM_207122
dbSNP: rs886041199
Type: Duplication
Location: chr11:44124950 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 303: 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

Also linked: seizures-scoliosis-macrocephaly syndrome

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT2 p.His303_Gln304insArgHisLysHis Uncertain significance ★★ same residue
EXT2 p.Asn161fs Pathogenic ★★ same condition
EXT2 p.Asp82fs Pathogenic ★★ same condition
EXT2 p.Met135fs Pathogenic ★★ same condition
EXT2 p.Ala392fs Pathogenic ★ same condition
EXT2 p.Asn578fs Pathogenic ★ same condition
EXT2 p.Glu397fs Pathogenic ★ same condition
EXT2 p.Gly225fs 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-his303fs (accessed [today's date]).

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