Is EXT1 p.Phe253Leu (c.757T>C) pathogenic?

EXT1 p.Phe253Leu (c.757T>C) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.4758); Very rare (popmax 0.00667%, amr); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Phe253Leu (c.757T>C)?

EXT1 p.Phe253Leu (c.757T>C) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Phe253Leu (c.757T>C) in the general population?

EXT1 p.Phe253Leu (c.757T>C) is very rare (popmax 0.00667%, amr) (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.Phe253Leu (c.757T>C)?

AlphaMissense predicts ambiguous (score 0.4758) — an in-silico prediction, not a clinical call.

EXT1 p.Phe253Leu

c.757T>C · rs1436385815 · VCV910035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
AlphaMissense	0.4758	ambiguous
REVEL	0.386	indeterminate
SaProt	LLR -5.09	tolerated
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	23.1	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 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,614,026 alleles · very rare exomes 4/1,461,894 · genomes 0/152,132 · 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: EXT1
Protein: p.Phe253Leu
Coding: c.757T>C
MANE Select: NM_000127
dbSNP: rs1436385815
Type: single nucleotide variant
Location: chr8:118110290 (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 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
EXT1 c.1418-2A>G 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-phe253leu (accessed [today's date]).

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