Is EXT2 p.Val593Leu (c.1777G>T) pathogenic?

EXT2 p.Val593Leu (c.1777G>T) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-08). AlphaMissense: likely pathogenic (0.9562); Very rare (popmax 0.00167%, amr); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Val593Leu (c.1777G>T)?

EXT2 p.Val593Leu (c.1777G>T) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Val593Leu (c.1777G>T) in the general population?

EXT2 p.Val593Leu (c.1777G>T) is very rare (popmax 0.00167%, 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 EXT2 p.Val593Leu (c.1777G>T)?

AlphaMissense predicts likely pathogenic (score 0.9562) — an in-silico prediction, not a clinical call.

EXT2 p.Val593Leu

c.1777G>T · rs1196840706 · VCV1954768

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.9562	likely pathogenic
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -11.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 37 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,014 alleles

Overall 0.000124% 2/1,614,036 alleles · very rare exomes 2/1,461,738 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
European (non-Finnish)	8.47e-05%	1,179,952

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: EXT2
Protein: p.Val593Leu
Coding: c.1777G>T
MANE Select: NM_207122
dbSNP: rs1196840706
Type: single nucleotide variant
Location: chr11:44232467 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 2 — 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

EXT2 p.Val593fs Likely pathogenic ★★ same residue
EXT2 c.1079+1G>A Pathogenic ★★ same condition
EXT2 c.1079+1G>T Pathogenic ★★ same condition
EXT2 c.1173+1G>A Pathogenic ★★ same condition
EXT2 c.1662+1G>C Likely pathogenic ★★ same condition
EXT2 c.536+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>C 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/ext2-p-val593leu (accessed [today's date]).

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