Is EXT1 p.Lys321Arg (c.962A>G) pathogenic?

EXT1 p.Lys321Arg (c.962A>G) is classified Uncertain significance in EXT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-21). AlphaMissense: likely benign (0.0668); Very rare (popmax 0.000593%, nfe); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Lys321Arg (c.962A>G)?

EXT1 p.Lys321Arg (c.962A>G) is associated with hereditary multiple osteochondromas, chondrosarcoma (ClinVar).

How common is EXT1 p.Lys321Arg (c.962A>G) in the general population?

EXT1 p.Lys321Arg (c.962A>G) is very rare (popmax 0.000593%, 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.Lys321Arg (c.962A>G)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

EXT1 p.Lys321Arg

c.962A>G · rs779587832 · VCV2170647

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 280 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,046 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,900 alleles · very rare exomes 6/1,461,726 · genomes 1/152,174 · joint denominator

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.Lys321Arg
Coding: c.962A>G
MANE Select: NM_000127
dbSNP: rs779587832
Type: single nucleotide variant
Location: chr8:118110085 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 321: 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

Also linked: chondrosarcoma

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT1 p.Lys321Ter Pathogenic ★ same residue
EXT1 p.Lys321= 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

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-lys321arg (accessed [today's date]).

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