Is EXT1 p.Arg83fs (c.247dup) pathogenic?

EXT1 p.Arg83fs (c.247dup) is classified Pathogenic in EXT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-27). Very rare (popmax 0.00133%, afr); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Arg83fs (c.247dup)?

EXT1 p.Arg83fs (c.247dup) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Arg83fs (c.247dup) in the general population?

EXT1 p.Arg83fs (c.247dup) 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.Arg83fs

c.247dup · rs1554601559 · VCV503617

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 6, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,946 alleles

Overall 0.000124% 2/1,613,404 alleles · very rare exomes 1/1,461,216 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-Americangrpmax	0.00133%	74,946

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg83fs
Coding: c.247dup
MANE Select: NM_000127
dbSNP: rs1554601559
Type: Duplication
Location: chr8:118110799 (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.Arg6fs Pathogenic ★★ same condition
EXT1 p.Asn446_Lys447insHisValThrValTer Pathogenic ★★ same condition
EXT1 p.His285fs Pathogenic ★★ same condition
EXT1 p.Ser478fs Pathogenic ★★ same condition
EXT1 p.Thr568fs Pathogenic ★★ same condition
EXT1 c.1417+2dup Likely pathogenic ★ same condition
EXT1 c.1632+1dup Pathogenic ★ same condition
EXT1 c.1722+2dup 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-arg83fs (accessed [today's date]).

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