Is CHST1 p.Pro223Arg (c.668C>G) pathogenic?

CHST1 p.Pro223Arg (c.668C>G) is classified Uncertain significance in CHST1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: ambiguous (0.4192); Very rare (popmax 0.00551%, nfe).

How common is CHST1 p.Pro223Arg (c.668C>G) in the general population?

CHST1 p.Pro223Arg (c.668C>G) is very rare (popmax 0.00551%, nfe) (gnomAD).

What do computational predictors say about CHST1 p.Pro223Arg (c.668C>G)?

AlphaMissense predicts ambiguous (score 0.4192) — an in-silico prediction, not a clinical call.

CHST1 p.Pro223Arg

c.668C>G · rs750719004 · VCV3144694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4192	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -8.23	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 1,232 bp · p 1.1e-08 · regional, not allelic
Overall
CADD	27.7	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 0.00551% European (non-Finnish) · 65/1,179,316 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00404%

Overall 0.00417% 67/1,607,254 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00551%	18,143
Remaining individualsnot grpmax-eligible	0.0016%	62,386
African / African-American	0.00134%	74,876

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: CHST1
Protein: p.Pro223Arg
Coding: c.668C>G
MANE Select: NM_003654
dbSNP: rs750719004
Type: single nucleotide variant
Location: chr11:45650256 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 87.90

Full CHST1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CHST1 p.Ala43Val Uncertain significance ★ ⚠ same type
CHST1 p.Ala54Thr Uncertain significance ★ ⚠ same type
CHST1 p.Arg114Gln Uncertain significance ★ ⚠ same type
CHST1 p.Arg198Ser Uncertain significance ★ ⚠ same type
CHST1 p.Arg217His Uncertain significance ★ ⚠ same type

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/chst1-p-pro223arg (accessed [today's date]).

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