Is EXT1 p.Pro535Ser (c.1603C>T) pathogenic?

EXT1 p.Pro535Ser (c.1603C>T) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). AlphaMissense: likely benign (0.2545); Very rare (popmax 0.00134%, afr); Associated with chondrosarcoma.

What condition is associated with EXT1 p.Pro535Ser (c.1603C>T)?

EXT1 p.Pro535Ser (c.1603C>T) is associated with chondrosarcoma (ClinVar).

How common is EXT1 p.Pro535Ser (c.1603C>T) in the general population?

EXT1 p.Pro535Ser (c.1603C>T) is very rare (popmax 0.00134%, 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.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.2545) — an in-silico prediction, not a clinical call.

EXT1 p.Pro535Ser

c.1603C>T · rs1006713733 · VCV3241449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.2545	likely benign
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -12.92	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	28.8	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 0.00134% African / African-American · 1/74,906 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00105% 17/1,614,032 alleles · very rare exomes 16/1,461,858 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-Americangrpmax	0.00134%	74,906
European (non-Finnish)	0.00119%	84,287

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.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_000127
dbSNP: rs1006713733
Type: single nucleotide variant
Location: chr8:117818464 (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

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.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
EXT1 p.Arg691His 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-pro535ser (accessed [today's date]).

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