Is EXT2 p.Ile403Thr (c.1208T>C) pathogenic?

EXT2 p.Ile403Thr (c.1208T>C) is classified Likely benign in EXT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-14). AlphaMissense: ambiguous (0.3897); Rare (popmax 0.232%, sas); Associated with exostoses, multiple, type 1.

What condition is associated with EXT2 p.Ile403Thr (c.1208T>C)?

EXT2 p.Ile403Thr (c.1208T>C) is associated with exostoses, multiple, type 1, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Ile403Thr (c.1208T>C) in the general population?

EXT2 p.Ile403Thr (c.1208T>C) is rare (popmax 0.232%, sas) (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.Ile403Thr (c.1208T>C)?

AlphaMissense predicts ambiguous (score 0.3897) — an in-silico prediction, not a clinical call.

EXT2 p.Ile403Thr

c.1208T>C · rs530523884 · VCV304588

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3897 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.232%, sas)

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
AlphaMissense	0.3897	ambiguous
REVEL	0.453	indeterminate
SaProt	LLR -4.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	23.9	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 0.232% South Asian · 211/91,078 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.196%

Overall 0.0144% 232/1,614,158 alleles · rare exomes 218/1,461,878 · genomes 14/152,280 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.232%	432
Remaining individualsnot grpmax-eligible	0.0288%	3,473
East Asian	0.00223%	44,870
African / African-American	0.00133%	75,042
European (non-Finnish)	8.47e-05%	1,180,020

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.Ile403Thr
Coding: c.1208T>C
MANE Select: NM_207122
dbSNP: rs530523884
Type: single nucleotide variant
Location: chr11:44171645 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 403: an α-helix

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 2

For Multiple osteochondromas (Orphanet):

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

Similar variants

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
EXT2 c.626+1G>T Pathogenic/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-ile403thr (accessed [today's date]).

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