Is EXT1 p.Arg340His (c.1019G>A) pathogenic?

EXT1 p.Arg340His (c.1019G>A) is classified Pathogenic in EXT1 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-03-01). AlphaMissense: likely pathogenic (0.9881); Very rare (popmax 0.00133%, afr); Associated with exostoses, multiple, type 1.

What condition is associated with EXT1 p.Arg340His (c.1019G>A)?

EXT1 p.Arg340His (c.1019G>A) is associated with exostoses, multiple, type 1, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Arg340His (c.1019G>A) in the general population?

EXT1 p.Arg340His (c.1019G>A) 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.

What do computational predictors say about EXT1 p.Arg340His (c.1019G>A)?

AlphaMissense predicts likely pathogenic (score 0.9881) — an in-silico prediction, not a clinical call.

EXT1 p.Arg340His

c.1019G>A · rs119103287 · VCV265129

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.9881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
AlphaMissense	0.9881	likely pathogenic ✓ concordant with ClinVar
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 280 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00133% African / African-American · 1/75,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,978 alleles · very rare exomes 4/1,461,710 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
European (non-Finnish)	0.000254%	393,303

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.Arg340His
Coding: c.1019G>A
MANE Select: NM_000127
dbSNP: rs119103287
Type: single nucleotide variant
Location: chr8:117837145 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 340: a UniProt-annotated variant site (in ext1; decreased glucuronosyl-n-acetylglucosaminyl-proteoglycan 4-alpha-n-acetylglucosaminyltransferase activity; decreased n-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity; loss of heparan sulfate proteoglycan biosynthetic process; no effect on interaction with ext2; can be integrated in heparan sulfate polymerase complex); a UniProt-annotated variant site (in ext1); a UniProt-annotated variant site (in ext1; loss of heparan sulfate proteoglycan biosynthetic process); 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

Also linked: hereditary multiple osteochondromas

For Multiple osteochondromas (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: >1 / 1000 (Specific population)

Similar variants

EXT1 p.Arg340Cys Pathogenic/Likely pathogenic ★★ same residue
EXT1 p.Arg340Gly Pathogenic/Likely pathogenic ★★ same residue
EXT1 p.Arg340Leu Pathogenic ★★ same residue
EXT1 p.Arg340= Benign ★ 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

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-arg340his (accessed [today's date]).

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