Is EXT1 p.Ser494Phe (c.1481C>T) pathogenic?

EXT1 p.Ser494Phe (c.1481C>T) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-07). AlphaMissense: likely pathogenic (0.698); Very rare (popmax 0.00534%, afr); Associated with exostoses, multiple, type 1.

What condition is associated with EXT1 p.Ser494Phe (c.1481C>T)?

EXT1 p.Ser494Phe (c.1481C>T) is associated with exostoses, multiple, type 1 (ClinVar).

How common is EXT1 p.Ser494Phe (c.1481C>T) in the general population?

EXT1 p.Ser494Phe (c.1481C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Multiple osteochondromas inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EXT1 p.Ser494Phe (c.1481C>T)?

AlphaMissense predicts likely pathogenic (score 0.698) — an in-silico prediction, not a clinical call.

EXT1 p.Ser494Phe

c.1481C>T · rs773877597 · VCV1710956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
AlphaMissense	0.698	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt 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 0.73, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	32.0	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 0.00534% African / African-American · 4/74,896 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,184 alleles · very rare exomes 1/1,461,000 · genomes 4/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,724
Admixed American	0.00167%	60,006

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.Ser494Phe
Coding: c.1481C>T
MANE Select: NM_000127
dbSNP: rs773877597
Type: single nucleotide variant
Location: chr8:117819731 (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

exostoses, multiple, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple osteochondromas (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: >1 / 1000 (Specific population)

Similar variants

EXT1 c.1418-1G>A Pathogenic ★★ same condition
EXT1 c.1418-2A>G Pathogenic ★★ same condition
EXT1 c.1536+1G>A Pathogenic ★★ same condition
EXT1 c.1723-2A>T Pathogenic/Likely pathogenic ★★ same condition
EXT1 c.1884-1G>C Pathogenic ★★ same condition
EXT1 c.962+1G>A Pathogenic ★★ same condition
EXT1 p.Arg280Gly Pathogenic ★★ same condition
EXT1 p.Arg340Cys Pathogenic/Likely 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-ser494phe (accessed [today's date]).

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