Is EXT1 p.Ala689= (c.2067T>G) pathogenic?

EXT1 p.Ala689= (c.2067T>G) is classified Likely benign in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-28). Very rare (popmax 0.00133%, afr); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Ala689= (c.2067T>G)?

EXT1 p.Ala689= (c.2067T>G) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Ala689= (c.2067T>G) in the general population?

EXT1 p.Ala689= (c.2067T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT1 p.Ala689=

c.2067T>G · rs1328284323 · VCV2978766

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -1.7, phastCons 1
Overall
CADD	9.496	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,918 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,613,934 alleles · very rare exomes 10/1,461,778 · genomes 1/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,918
European (non-Finnish)	0.000847%	118,003

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.Ala689=
Coding: c.2067T>G
MANE Select: NM_000127
dbSNP: rs1328284323
Type: single nucleotide variant
Location: chr8:117799886 (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 p.Ala689Thr Uncertain significance ★★ ⚠ same residue
EXT1 p.Ala689Ser Uncertain significance ★ ⚠ same residue
EXT1 p.Ala689fs Pathogenic ★ 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

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-ala689 (accessed [today's date]).

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