Is EXT1 p.Arg688Trp (c.2062C>T) pathogenic?

EXT1 p.Arg688Trp (c.2062C>T) is classified Conflicting classifications of pathogenicity in EXT1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-14). AlphaMissense: likely pathogenic (0.8269); Ultra-rare (popmax 0.0196%, nfe); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Arg688Trp (c.2062C>T)?

EXT1 p.Arg688Trp (c.2062C>T) is associated with hereditary multiple osteochondromas, exostoses, multiple, type 1, ovarian cancer (ClinVar).

How common is EXT1 p.Arg688Trp (c.2062C>T) in the general population?

EXT1 p.Arg688Trp (c.2062C>T) is ultra-rare (popmax 0.0196%, nfe) (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.Arg688Trp (c.2062C>T)?

AlphaMissense predicts likely pathogenic (score 0.8269) — an in-silico prediction, not a clinical call.

EXT1 p.Arg688Trp

c.2062C>T · rs138855109 · VCV1548975

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
AlphaMissense	0.8269	likely pathogenic
REVEL	0.449	indeterminate
SaProt	LLR -10.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 13 kb · p 1.9e-10 · regional, not allelic
Overall
CADD	33.0	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 0.0196% European (non-Finnish) · 231/1,180,032 alleles

Filtering AF 0.0175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.0156% 251/1,613,866 alleles · ultra-rare exomes 243/1,461,724 · genomes 8/152,142 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0196%	5,108
East Asian	0.0156%	6,413
South Asian	0.00988%	10,119
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00267%	37,455

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.Arg688Trp
Coding: c.2062C>T
MANE Select: NM_000127
dbSNP: rs138855109
Type: single nucleotide variant
Location: chr8:117799891 (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

hereditary multiple osteochondromas — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 1 ovarian cancer

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT1 p.Arg688Gln 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
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-arg688trp (accessed [today's date]).

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