Is EXT1 p.Leu562Pro (c.1685T>C) pathogenic?

EXT1 p.Leu562Pro (c.1685T>C) is classified Pathogenic in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Leu562Pro (c.1685T>C)?

EXT1 p.Leu562Pro (c.1685T>C) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Leu562Pro (c.1685T>C) in the general population?

EXT1 p.Leu562Pro (c.1685T>C) is absent from gnomAD v4.1 (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.Leu562Pro (c.1685T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

EXT1 p.Leu562Pro

c.1685T>C · rs2129720069 · VCV2136694

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 3% in EXT1
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -15.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EXT1
Protein: p.Leu562Pro
Coding: c.1685T>C
MANE Select: NM_000127
dbSNP: rs2129720069
Type: single nucleotide variant
Location: chr8:117812909 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 562: a β-strand

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-leu562pro (accessed [today's date]).

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