Is CHST3 p.Pro126Gln (c.377C>A) pathogenic?

CHST3 p.Pro126Gln (c.377C>A) is classified Uncertain significance in CHST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-31). AlphaMissense: likely benign (0.0767); Very rare (popmax 0.00221%, sas); Associated with spondyloepiphyseal dysplasia with congenital joint dislocations.

What condition is associated with CHST3 p.Pro126Gln (c.377C>A)?

CHST3 p.Pro126Gln (c.377C>A) is associated with spondyloepiphyseal dysplasia with congenital joint dislocations (ClinVar).

How common is CHST3 p.Pro126Gln (c.377C>A) in the general population?

CHST3 p.Pro126Gln (c.377C>A) is very rare (popmax 0.00221%, sas) (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.Pro126Gln (c.377C>A)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

CHST3 p.Pro126Gln

c.377C>A · rs371091098 · VCV1521785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepiphyseal dysplasia with congenital joint dislocations

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -8.05	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 -0.41	GERP -0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 2,625 bp · p 0.38 · regional, not allelic
Overall
CADD	3.09	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 0.00221% South Asian · 2/90,578 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000138% 2/1,452,802 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.Pro126Gln
Coding: c.377C>A
MANE Select: NM_004273
dbSNP: rs371091098
Type: single nucleotide variant
Location: chr10:72007408 (GRCh38)
Gene constraint: LOEUF 1.119 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.58
Residue 126: the 'disordered' region

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.Pro126Leu Uncertain significance ★ ⚠ same residue
CHST3 p.Pro126= Likely benign ★ same residue
CHST3 p.Pro126Ala Uncertain significance ★ ⚠ same residue
CHST3 p.Pro126Arg Uncertain significance ★ ⚠ 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

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-pro126gln (accessed [today's date]).

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