Is CHST14 p.Arg274Pro (c.821G>C) pathogenic?

CHST14 p.Arg274Pro (c.821G>C) is classified Pathogenic in CHST14 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2012-06-01). AlphaMissense: likely pathogenic (0.7957); Very rare (popmax 0.000339%, nfe); Associated with Ehlers-Danlos syndrome, musculocontractural type 1.

What condition is associated with CHST14 p.Arg274Pro (c.821G>C)?

CHST14 p.Arg274Pro (c.821G>C) is associated with Ehlers-Danlos syndrome, musculocontractural type 1 (ClinVar).

How common is CHST14 p.Arg274Pro (c.821G>C) in the general population?

CHST14 p.Arg274Pro (c.821G>C) is very rare (popmax 0.000339%, nfe) (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.Arg274Pro (c.821G>C)?

AlphaMissense predicts likely pathogenic (score 0.7957) — an in-silico prediction, not a clinical call.

CHST14 p.Arg274Pro

c.821G>C · rs397514706 · VCV50992

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, musculocontractural type 1

Computational evidence

Protein change
AlphaMissense	0.7957	likely pathogenic ✓ concordant with ClinVar
REVEL	0.348	indeterminate
SaProt	LLR -12.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.44, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,127 bp · p 0.038 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,032 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)grpmax	0.000339%	295,008

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg274Pro
Coding: c.821G>C
MANE Select: NM_130468
dbSNP: rs397514706
Type: single nucleotide variant
Location: chr15:40472034 (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 1 — 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.Arg274= Likely benign ★★ same residue
CHST14 p.Arg213Pro Likely pathogenic ★★ same condition
CHST14 p.Glu262Lys Pathogenic/Likely pathogenic ★★ same condition
CHST14 p.Tyr293Cys Pathogenic/Likely pathogenic ★★ same condition
CHST14 p.Asp99Asn Uncertain significance ★★ ⚠ same condition
CHST14 p.Glu311Asp Uncertain significance ★★ ⚠ same condition
CHST14 p.Thr7Asn Uncertain significance ★★ ⚠ same condition
CHST14 p.Gln308Ter 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/chst14-p-arg274pro (accessed [today's date]).

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