Is EXT1 p.Pro477= (c.1431C>T) pathogenic?

EXT1 p.Pro477= (c.1431C>T) is classified Benign in EXT1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 20%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with exostoses, multiple, type 1.

What condition is associated with EXT1 p.Pro477= (c.1431C>T)?

EXT1 p.Pro477= (c.1431C>T) is associated with exostoses, multiple, type 1, hereditary multiple osteochondromas (ClinVar).

How is Multiple osteochondromas inherited?

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

EXT1 p.Pro477=

Q: How common is EXT1 p.Pro477= (c.1431C>T) in the general population?

EXT1 p.Pro477= (c.1431C>T) is common (popmax 20%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1431C>T · rs17439693 · VCV255172

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 20%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -1.9, phastCons 0.84
Overall
CADD	6.394	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20% European (non-Finnish) · 235,460/1,178,688 alleles

Filtering AF 19.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.9%

Overall 18.8% 303,597/1,611,950 alleles · common exomes 277,351/1,459,842 · genomes 26,246/152,108 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	30.6%	3
Amishnot grpmax-eligible	20.6%	5
European (non-Finnish)grpmax	20%	5
Admixed American	18.4%	5
Remaining individualsnot grpmax-eligible	18.2%	5
Middle Eastern	17%	6
Ashkenazi Jewishnot grpmax-eligible	14.8%	7
South Asian	12.4%	8
African / African-American	10.3%	10
East Asian	3.77%	27

Finnish 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.Pro477=
Coding: c.1431C>T
MANE Select: NM_000127
dbSNP: rs17439693
Type: single nucleotide variant
Location: chr8:117819781 (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

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

Also linked: hereditary multiple osteochondromas

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT1 p.Pro477Ala Uncertain significance ★ ⚠ same residue
EXT1 p.Pro477Arg Conflicting classifications of pathogenicity ★ ⚠ 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-pro477 (accessed [today's date]).

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