Is EXT1 p.Ile256= (c.768C>T) pathogenic?

EXT1 p.Ile256= (c.768C>T) is classified Likely benign in EXT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0557%, eas); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Ile256= (c.768C>T)?

EXT1 p.Ile256= (c.768C>T) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Ile256= (c.768C>T) in the general population?

EXT1 p.Ile256= (c.768C>T) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT1 p.Ile256=

c.768C>T · rs566692634 · VCV739330

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.062	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 4.1, phastCons 1
Overall
CADD	10.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0557% East Asian · 25/44,876 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00186% 30/1,614,078 alleles · ultra-rare exomes 25/1,461,892 · genomes 5/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,795
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.000169%	590,005

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: EXT1
Protein: p.Ile256=
Coding: c.768C>T
MANE Select: NM_000127
dbSNP: rs566692634
Type: single nucleotide variant
Location: chr8:118110279 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB

Full EXT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary multiple osteochondromas — 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

EXT1 p.Ile256Val Uncertain significance ★ ⚠ same residue
EXT1 c.1056+1G>A Pathogenic ★★ same condition
EXT1 c.1056+1G>T Pathogenic ★★ same condition
EXT1 c.1165-1G>A Pathogenic ★★ same condition
EXT1 c.1285-1G>C Pathogenic ★★ same condition
EXT1 c.1417+1G>A Pathogenic ★★ same condition
EXT1 c.1417+1G>T Pathogenic ★★ same condition
EXT1 c.1418-1G>A 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/ext1-p-ile256 (accessed [today's date]).

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