Is EXT1 p.Pro477Arg (c.1430C>G) pathogenic?

EXT1 p.Pro477Arg (c.1430C>G) is classified Conflicting classifications of pathogenicity in EXT1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1018); Very rare (popmax 0.00653%, nfe); Associated with chondrosarcoma.

What condition is associated with EXT1 p.Pro477Arg (c.1430C>G)?

EXT1 p.Pro477Arg (c.1430C>G) is associated with chondrosarcoma, hereditary multiple osteochondromas, exostoses, multiple, type 1 (ClinVar).

How common is EXT1 p.Pro477Arg (c.1430C>G) in the general population?

EXT1 p.Pro477Arg (c.1430C>G) is very rare (popmax 0.00653%, nfe) (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.Pro477Arg (c.1430C>G)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

EXT1 p.Pro477Arg

c.1430C>G · rs145720047 · VCV134201

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -8.86	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	21.5	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 0.00653% European (non-Finnish) · 77/1,179,896 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00589% 95/1,613,260 alleles · very rare exomes 81/1,461,068 · genomes 14/152,192 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
European (non-Finnish)grpmax	0.00653%	15,323
Admixed American	0.00333%	29,998
Remaining individualsnot grpmax-eligible	0.0032%	31,216
African / African-American	0.00133%	74,908

Ashkenazi Jewish 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.Pro477Arg
Coding: c.1430C>G
MANE Select: NM_000127
dbSNP: rs145720047
Type: single nucleotide variant
Location: chr8:117819782 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 477: 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

Also linked: hereditary multiple osteochondromas exostoses, multiple, type 1

For Chondrosarcoma (Orphanet):

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

Similar variants

EXT1 p.Pro477= Benign ★★ same residue
EXT1 p.Pro477Ala Uncertain significance ★ ⚠ same residue
EXT1 p.Pro477Leu Uncertain significance ★ ⚠ same residue
EXT1 p.Pro477Thr 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

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-pro477arg (accessed [today's date]).

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