Is EXT1 p.Arg528Cys (c.1582C>T) pathogenic?

EXT1 p.Arg528Cys (c.1582C>T) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-07). AlphaMissense: likely pathogenic (0.8017); Very rare (popmax 0.00133%, afr); Associated with chondrosarcoma.

What condition is associated with EXT1 p.Arg528Cys (c.1582C>T)?

EXT1 p.Arg528Cys (c.1582C>T) is associated with chondrosarcoma (ClinVar).

How common is EXT1 p.Arg528Cys (c.1582C>T) in the general population?

EXT1 p.Arg528Cys (c.1582C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Chondrosarcoma inherited?

Typically Not applicable, Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EXT1 p.Arg528Cys (c.1582C>T)?

AlphaMissense predicts likely pathogenic (score 0.8017) — an in-silico prediction, not a clinical call.

EXT1 p.Arg528Cys

c.1582C>T · rs761451875 · VCV2675157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.8017	likely pathogenic
REVEL	0.719	pathogenic-leaning
SaProt	LLR -7.51	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	34.0	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 · 1/74,996 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,024 alleles · very rare exomes 7/1,461,854 · genomes 0/152,170 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-Americangrpmax	0.00133%	74,996
European (non-Finnish)	0.000424%	235,997

Finnish 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.Arg528Cys
Coding: c.1582C>T
MANE Select: NM_000127
dbSNP: rs761451875
Type: single nucleotide variant
Location: chr8:117818485 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 528: an α-helix

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

Disease context

chondrosarcoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Chondrosarcoma (Orphanet):

Inheritance: Not applicable, Unknown
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

EXT1 p.Arg528His Uncertain significance ★ same residue
EXT1 p.Arg340Cys Pathogenic/Likely pathogenic ★★ same condition
EXT1 p.Arg340Leu Pathogenic ★★ same condition
EXT1 p.Gln2Ter Pathogenic ★★ same condition
EXT1 p.Ala689Thr Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg188Ser Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg325Trp Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg384Lys Uncertain significance ★★ ⚠ 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-arg528cys (accessed [today's date]).

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