Is EXT1 p.Cys355= (c.1065C>T) pathogenic?

EXT1 p.Cys355= (c.1065C>T) is classified Benign in EXT1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 32.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with exostoses, multiple, type 1.

What condition is associated with EXT1 p.Cys355= (c.1065C>T)?

EXT1 p.Cys355= (c.1065C>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.Cys355=

Q: How common is EXT1 p.Cys355= (c.1065C>T) in the general population?

EXT1 p.Cys355= (c.1065C>T) is common (popmax 32.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1065C>T · rs11546829 · VCV196215

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 32.9%, mid) — 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.
REVEL	0.286	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.01	GERP -3.7, phastCons 0.076
Overall
CADD	7.817	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 32.9% Middle Eastern · 1,995/6,056 alleles

Filtering AF 32% ClinGen BA1/BS1 input FAF95, joint · FAF99 31.8%

Overall 27.7% 445,944/1,610,886 alleles · common exomes 410,007/1,458,772 · genomes 35,937/152,114 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	32.9%	3
Admixed American	32.3%	3
Ashkenazi Jewishnot grpmax-eligible	29.8%	3
European (non-Finnish)	29.5%	3
Remaining individualsnot grpmax-eligible	27.4%	4
Amishnot grpmax-eligible	25.2%	4
Finnishnot grpmax-eligible	24.8%	4
South Asian	24.7%	4
African / African-American	12.4%	8
East Asian	8.87%	11

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.Cys355=
Coding: c.1065C>T
MANE Select: NM_000127
dbSNP: rs11546829
Type: single nucleotide variant
Location: chr8:117835543 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 355: a disulfide bond

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.Cys355Arg Pathogenic/Likely pathogenic ★★ same residue
EXT1 p.Cys355Ter Pathogenic ★ same residue
EXT1 p.Cys355Trp Pathogenic ★ same residue
EXT1 p.Cys355Tyr Pathogenic ★ 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-cys355 (accessed [today's date]).

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