Is CHST1 p.Leu42Pro (c.125T>C) pathogenic?

CHST1 p.Leu42Pro (c.125T>C) is classified Uncertain significance in CHST1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely benign (0.0535); Very rare (popmax 0.00322%, nfe).

How common is CHST1 p.Leu42Pro (c.125T>C) in the general population?

CHST1 p.Leu42Pro (c.125T>C) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about CHST1 p.Leu42Pro (c.125T>C)?

AlphaMissense predicts likely benign (score 0.0535) — an in-silico prediction, not a clinical call.

CHST1 p.Leu42Pro

c.125T>C · VCV4002696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0535	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP -2.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 1,232 bp · p 1.1e-08 · regional, not allelic
Overall
CADD	17.77	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 0.00322% European (non-Finnish) · 38/1,179,518 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00242% 39/1,613,116 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,040
Remaining individualsnot grpmax-eligible	0.0016%	62,446

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.Leu42Pro
Coding: c.125T>C
MANE Select: NM_003654
Type: single nucleotide variant
Location: chr11:45650799 (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

CHST1 p.Arg59His Uncertain significance ★★ ⚠ same type
CHST1 p.Ala12Thr Uncertain significance ★ ⚠ same type
CHST1 p.Ala388Thr Uncertain significance ★ ⚠ same type
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-leu42pro (accessed [today's date]).

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