Is EXT1 p.Leu452= (c.1354T>C) pathogenic?

EXT1 p.Leu452= (c.1354T>C) is classified Likely benign in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). Ultra-rare (popmax 0.0111%, eas); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Leu452= (c.1354T>C)?

EXT1 p.Leu452= (c.1354T>C) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Leu452= (c.1354T>C) in the general population?

EXT1 p.Leu452= (c.1354T>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT1 p.Leu452=

c.1354T>C · rs1372000855 · VCV732856

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.66, phastCons 1
Overall
CADD	7.348	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,854 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000496% 8/1,613,202 alleles · ultra-rare exomes 7/1,460,998 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,971
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.00017%	589,776

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.Leu452=
Coding: c.1354T>C
MANE Select: NM_000127
dbSNP: rs1372000855
Type: single nucleotide variant
Location: chr8:117822528 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 452: a turn

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.Leu452Trp 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-leu452 (accessed [today's date]).

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