Is EXT1 p.Val537= (c.1611C>T) pathogenic?

EXT1 p.Val537= (c.1611C>T) is classified Likely benign in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). Very rare (popmax 0.00223%, eas); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Val537= (c.1611C>T)?

EXT1 p.Val537= (c.1611C>T) is associated with hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Val537= (c.1611C>T) in the general population?

EXT1 p.Val537= (c.1611C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Multiple osteochondromas inherited?

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

EXT1 p.Val537=

c.1611C>T · rs772636953 · VCV2741852

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary multiple osteochondromas

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 0.007	GERP -1.2, phastCons 0.28
Overall
CADD	10.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,613,960 alleles · very rare exomes 17/1,461,846 · genomes 2/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
Admixed American	0.00167%	59,994
European (non-Finnish)	0.00144%	69,412

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.Val537=
Coding: c.1611C>T
MANE Select: NM_000127
dbSNP: rs772636953
Type: single nucleotide variant
Location: chr8:117818456 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 537: a β-strand

Full EXT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary multiple osteochondromas — 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 p.Val537Ile Conflicting classifications of pathogenicity ★ ⚠ 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
EXT1 c.1417+1G>A Pathogenic ★★ same condition
EXT1 c.1417+1G>T Pathogenic ★★ same condition
EXT1 c.1418-1G>A 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-val537 (accessed [today's date]).

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