Is CHST4 p.Leu22Pro (c.65T>C) pathogenic?

CHST4 p.Leu22Pro (c.65T>C) is classified Uncertain significance in CHST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.2949); Very rare (popmax 0.00704%, amr).

How common is CHST4 p.Leu22Pro (c.65T>C) in the general population?

CHST4 p.Leu22Pro (c.65T>C) is very rare (popmax 0.00704%, amr) (gnomAD).

What do computational predictors say about CHST4 p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.2949) — an in-silico prediction, not a clinical call.

CHST4 p.Leu22Pro

c.65T>C · VCV4653673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00704%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2949	likely benign
REVEL	0.619	indeterminate
SaProt	LLR -13.92	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 1,157 bp · p 0.075 · regional, not allelic
Overall
CADD	23.4	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 0.00704% Admixed American · 3/42,620 alleles

Filtering AF 0.00187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00102%

Overall 0.000199% 3/1,503,804 alleles · very rare exomes 3/1,351,446 · genomes 0/152,358 · joint denominator

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: CHST4
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_001166395
Type: single nucleotide variant
Location: chr16:71536742 (GRCh38)
Gene constraint: LOEUF 1.836 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 90.66

Full CHST4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHST4 p.Ala135Val Uncertain significance ★ ⚠ same type
CHST4 p.Ala167Ser Uncertain significance ★ ⚠ same type
CHST4 p.Ala18Ser Uncertain significance ★ ⚠ same type
CHST4 p.Ala18Thr Uncertain significance ★ ⚠ same type
CHST4 p.Ala333Val Uncertain significance ★ ⚠ same type
CHST4 p.Arg118Gln Uncertain significance ★ ⚠ same type
CHST4 p.Arg130Gln Uncertain significance ★ ⚠ same type
CHST4 p.Arg130Trp 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/chst4-p-leu22pro (accessed [today's date]).

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