Is EXT1 p.Lys321= (c.963G>A) pathogenic?

EXT1 p.Lys321= (c.963G>A) is classified Conflicting classifications of pathogenicity in EXT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-06). Very rare (popmax 0.00356%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Lys321= (c.963G>A)?

EXT1 p.Lys321= (c.963G>A) is associated with Inborn genetic diseases, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Lys321= (c.963G>A) in the general population?

EXT1 p.Lys321= (c.963G>A) is very rare (popmax 0.00356%, nfe) (gnomAD).

EXT1 p.Lys321=

c.963G>A · rs150109153 · VCV2054470

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.156	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.7, phastCons 1
Overall
CADD	14.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,178,604 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00237%

Overall 0.00273% 44/1,612,228 alleles · very rare exomes 42/1,460,180 · genomes 2/152,048 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,062
Remaining individualsnot grpmax-eligible	0.0016%	62,416
South Asian	0.0011%	91,004

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.Lys321=
Coding: c.963G>A
MANE Select: NM_000127
dbSNP: rs150109153
Type: single nucleotide variant
Location: chr8:117837201 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary multiple osteochondromas

Similar variants

EXT1 p.Lys321Arg Uncertain significance ★★ ⚠ same residue
EXT1 p.Lys321Ter 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
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-lys321 (accessed [today's date]).

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