Is CHST3 p.Ala129Glu (c.386C>A) pathogenic?

CHST3 p.Ala129Glu (c.386C>A) is classified Uncertain significance in CHST3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-17). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00034%, nfe); Associated with spondyloepiphyseal dysplasia with congenital joint dislocations.

What condition is associated with CHST3 p.Ala129Glu (c.386C>A)?

CHST3 p.Ala129Glu (c.386C>A) is associated with spondyloepiphyseal dysplasia with congenital joint dislocations (ClinVar).

How common is CHST3 p.Ala129Glu (c.386C>A) in the general population?

CHST3 p.Ala129Glu (c.386C>A) is very rare (popmax 0.00034%, nfe) (gnomAD).

How is CHST3-related skeletal dysplasia inherited?

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

What do computational predictors say about CHST3 p.Ala129Glu (c.386C>A)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

CHST3 p.Ala129Glu

c.386C>A · rs147535559 · VCV2906097

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepiphyseal dysplasia with congenital joint dislocations

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.61, phastCons 0.006
Regional constraint	o/e 1.03	unconstrained · MANE · 2,625 bp · p 0.38 · regional, not allelic
Overall
CADD	7.051	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 0.00034% European (non-Finnish) · 4/1,178,120 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000276% 4/1,450,848 alleles · very rare

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: CHST3
Protein: p.Ala129Glu
Coding: c.386C>A
MANE Select: NM_004273
dbSNP: rs147535559
Type: single nucleotide variant
Location: chr10:72007417 (GRCh38)
Gene constraint: LOEUF 1.119 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.58

Full CHST3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondyloepiphyseal dysplasia with congenital joint dislocations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CHST3-related skeletal dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

CHST3 p.Ala129Val Uncertain significance ★ ⚠ same residue
CHST3 p.Ala129= Likely benign ★ same residue
CHST3 p.Arg221Cys Pathogenic/Likely pathogenic ★★ same condition
CHST3 p.Glu230Ter Pathogenic/Likely pathogenic ★★ same condition
CHST3 p.Phe159Ile Pathogenic/Likely pathogenic ★★ same condition
CHST3 c.*57G>T Uncertain significance ★★ same condition
CHST3 c.*66G>T Uncertain significance ★★ same condition
CHST3 p.Ala106Thr Uncertain significance ★★ ⚠ 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/chst3-p-ala129glu (accessed [today's date]).

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