Is CHST5 p.Met22Ile (c.66G>A) pathogenic?

CHST5 p.Met22Ile (c.66G>A) is classified Uncertain significance in CHST5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: ambiguous (0.4094); Ultra-rare (popmax 0.0645%, nfe).

How common is CHST5 p.Met22Ile (c.66G>A) in the general population?

CHST5 p.Met22Ile (c.66G>A) is ultra-rare (popmax 0.0645%, nfe) (gnomAD).

What do computational predictors say about CHST5 p.Met22Ile (c.66G>A)?

AlphaMissense predicts ambiguous (score 0.4094) — an in-silico prediction, not a clinical call.

CHST5 p.Met22Ile

c.66G>A · VCV3267237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4094 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0645%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4094	ambiguous
REVEL	0.324	indeterminate
SaProt	LLR -7.46	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,232 bp · p 0.16 · regional, not allelic
Overall
CADD	16.67	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 0.0645% European (non-Finnish) · 759/1,176,206 alleles

Filtering AF 0.0607% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0592%

Overall 0.05% 802/1,604,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0645%	1,550
Remaining individualsnot grpmax-eligible	0.0322%	3,105
Finnishnot grpmax-eligible	0.0144%	6,954
African / African-American	0.0133%	7,495
Admixed American	0.00684%	14,616

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: CHST5
Protein: p.Met22Ile
Coding: c.66G>A
MANE Select: NM_024533
Type: single nucleotide variant
Location: chr16:75530319 (GRCh38)
Gene constraint: LOEUF 1.549 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 88.60

Full CHST5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHST5 p.Ala311Thr Benign ★★ same type
CHST5 p.Arg6Trp Benign ★★ ⚠ same type
CHST5 p.Glu322Gln Benign ★★ same type
CHST5 p.Ala11Val Uncertain significance ★ ⚠ same type
CHST5 p.Ala150Glu Uncertain significance ★ ⚠ same type
CHST5 p.Ala159Thr Uncertain significance ★ ⚠ same type
CHST5 p.Ala214Thr Uncertain significance ★ ⚠ same type
CHST5 p.Ala275Ser 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/chst5-p-met22ile (accessed [today's date]).

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