Is EXT1 p.Phe250Ile (c.748T>A) pathogenic?

EXT1 p.Phe250Ile (c.748T>A) is classified Uncertain significance in EXT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.2431); Ultra-rare (popmax 0.0283%, afr); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Phe250Ile (c.748T>A)?

EXT1 p.Phe250Ile (c.748T>A) is associated with hereditary multiple osteochondromas, exostoses, multiple, type 1 (ClinVar).

How common is EXT1 p.Phe250Ile (c.748T>A) in the general population?

EXT1 p.Phe250Ile (c.748T>A) is ultra-rare (popmax 0.0283%, afr) (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 EXT1 p.Phe250Ile (c.748T>A)?

AlphaMissense predicts likely benign (score 0.2431) — an in-silico prediction, not a clinical call.

EXT1 p.Phe250Ile

c.748T>A · rs920291906 · VCV1435161

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2431 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
AlphaMissense	0.2431	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 280 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% African / African-American · 21/74,116 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.00155% 25/1,612,046 alleles · ultra-rare exomes 15/1,461,892 · genomes 10/150,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0283%	3,529
Remaining individualsnot grpmax-eligible	0.0032%	31,224
South Asian	0.0011%	90,974
European (non-Finnish)	8.48e-05%	1,179,646

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.Phe250Ile
Coding: c.748T>A
MANE Select: NM_000127
dbSNP: rs920291906
Type: single nucleotide variant
Location: chr8:118110299 (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

Also linked: exostoses, multiple, type 1

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT1 p.Phe250_Leu251insTer Pathogenic ★★ same residue
EXT1 p.Phe250fs Pathogenic ★ 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

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-phe250ile (accessed [today's date]).

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