Is EXT1 p.Val502Met (c.1504G>A) pathogenic?

EXT1 p.Val502Met (c.1504G>A) is classified Uncertain significance in EXT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.00134%, afr); Associated with chondrosarcoma.

What condition is associated with EXT1 p.Val502Met (c.1504G>A)?

EXT1 p.Val502Met (c.1504G>A) is associated with chondrosarcoma, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Val502Met (c.1504G>A) in the general population?

EXT1 p.Val502Met (c.1504G>A) 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.Val502Met (c.1504G>A)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

EXT1 p.Val502Met

c.1504G>A · rs778048374 · VCV1412617

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.381	indeterminate
SaProt	LLR -5.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.74, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	21.8	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 0.00134% African / African-American · 1/74,846 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00093% 15/1,612,648 alleles · very rare exomes 14/1,460,554 · genomes 1/152,094 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,378
African / African-Americangrpmax	0.00134%	74,846
South Asian	0.0011%	91,014
European (non-Finnish)	0.00102%	98,335

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.Val502Met
Coding: c.1504G>A
MANE Select: NM_000127
dbSNP: rs778048374
Type: single nucleotide variant
Location: chr8:117819708 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 502: 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

For Chondrosarcoma (Orphanet):

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

Similar variants

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
EXT1 c.1418-2A>G 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-val502met (accessed [today's date]).

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