Is CHST14 p.Leu22Pro (c.65T>C) pathogenic?

CHST14 p.Leu22Pro (c.65T>C) is classified Uncertain significance in CHST14 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). AlphaMissense: likely benign (0.0474); Very rare (popmax 0.00123%, sas); Associated with Ehlers-Danlos syndrome, musculocontractural type.

What condition is associated with CHST14 p.Leu22Pro (c.65T>C)?

CHST14 p.Leu22Pro (c.65T>C) is associated with Ehlers-Danlos syndrome, musculocontractural type (ClinVar).

How common is CHST14 p.Leu22Pro (c.65T>C) in the general population?

CHST14 p.Leu22Pro (c.65T>C) is very rare (popmax 0.00123%, sas) (gnomAD).

How is Musculocontractural Ehlers-Danlos syndrome inherited?

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

What do computational predictors say about CHST14 p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.0474) — an in-silico prediction, not a clinical call.

CHST14 p.Leu22Pro

c.65T>C · rs2543005242 · VCV1957622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0474 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, musculocontractural type

Computational evidence

Protein change
AlphaMissense	0.0474	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -5.16	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 0.047	GERP -2
Regional constraint	o/e 0.91	unconstrained · MANE · 1,127 bp · p 0.038 · regional, not allelic
Overall
CADD	13.64	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 0.00123% South Asian · 1/81,292 alleles

Overall 0.000148% 2/1,353,554 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00123%	81,292
European (non-Finnish)	8.81e-05%	1,135,302

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: CHST14
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_130468
dbSNP: rs2543005242
Type: single nucleotide variant
Location: chr15:40471278 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.17

Full CHST14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, musculocontractural type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Musculocontractural Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CHST14 p.Arg213Pro Likely pathogenic ★★ same condition
CHST14 p.Arg320Ter Likely pathogenic ★★ same condition
CHST14 p.Gln204Ter Pathogenic/Likely pathogenic ★★ same condition
CHST14 p.Glu262Lys Pathogenic/Likely pathogenic ★★ same condition
CHST14 p.Tyr293Cys Pathogenic/Likely pathogenic ★★ same condition
CHST14 p.Ala11Val Uncertain significance ★★ ⚠ same condition
CHST14 p.Ala15Pro Uncertain significance ★★ ⚠ same condition
CHST14 p.Ala290Val 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/chst14-p-leu22pro (accessed [today's date]).

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