Is EXT1 p.Pro67His (c.200C>A) pathogenic?

EXT1 p.Pro67His (c.200C>A) is classified Uncertain significance in EXT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-04). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.00446%, eas); Associated with chondrosarcoma.

What condition is associated with EXT1 p.Pro67His (c.200C>A)?

EXT1 p.Pro67His (c.200C>A) is associated with chondrosarcoma, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Pro67His (c.200C>A) in the general population?

EXT1 p.Pro67His (c.200C>A) is very rare (popmax 0.00446%, eas) (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.Pro67His (c.200C>A)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

EXT1 p.Pro67His

c.200C>A · rs371817652 · VCV1345908

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.51	indeterminate
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 5.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 371 bp · p 0.2 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00105% 17/1,612,372 alleles · very rare exomes 15/1,460,214 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
European (non-Finnish)	0.00127%	78,587

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.Pro67His
Coding: c.200C>A
MANE Select: NM_000127
dbSNP: rs371817652
Type: single nucleotide variant
Location: chr8:118110847 (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

Also linked: hereditary multiple osteochondromas

For Chondrosarcoma (Orphanet):

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

Similar variants

EXT1 p.Pro67Arg Uncertain significance ★★ ⚠ 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
EXT1 c.1417+1G>T Pathogenic ★★ same condition
EXT1 c.1418-1G>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-pro67his (accessed [today's date]).

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