Is EXT1 p.Val672Ala (c.2015T>C) pathogenic?

EXT1 p.Val672Ala (c.2015T>C) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: likely pathogenic (0.9907); Absent from gnomAD v4.1; Associated with exostoses, multiple, type 1.

What condition is associated with EXT1 p.Val672Ala (c.2015T>C)?

EXT1 p.Val672Ala (c.2015T>C) is associated with exostoses, multiple, type 1 (ClinVar).

How common is EXT1 p.Val672Ala (c.2015T>C) in the general population?

EXT1 p.Val672Ala (c.2015T>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.Val672Ala (c.2015T>C)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

EXT1 p.Val672Ala

c.2015T>C · VCV4056279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -13.02	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 13 kb · p 1.9e-10 · regional, not allelic
Overall
CADD	29.0	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

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.Val672Ala
Coding: c.2015T>C
MANE Select: NM_000127
Type: single nucleotide variant
Location: chr8:117804762 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 672: a β-strand

Full EXT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 1 — 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.Val672= Likely benign ★ same residue
EXT1 c.1418-1G>A Pathogenic ★★ same condition
EXT1 c.1418-2A>G Pathogenic ★★ same condition
EXT1 c.1536+1G>A Pathogenic ★★ same condition
EXT1 c.1723-2A>T Pathogenic/Likely pathogenic ★★ same condition
EXT1 c.1884-1G>C Pathogenic ★★ same condition
EXT1 c.962+1G>A Pathogenic ★★ same condition
EXT1 p.Arg280Gly 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-val672ala (accessed [today's date]).

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