Is CHI3L2 p.Ser57Pro (c.169T>C) pathogenic?

CHI3L2 p.Ser57Pro (c.169T>C) is classified Uncertain significance in CHI3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). AlphaMissense: likely pathogenic (0.7398); Ultra-rare (popmax 0.0267%, eas).

How common is CHI3L2 p.Ser57Pro (c.169T>C) in the general population?

CHI3L2 p.Ser57Pro (c.169T>C) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about CHI3L2 p.Ser57Pro (c.169T>C)?

AlphaMissense predicts likely pathogenic (score 0.7398) — an in-silico prediction, not a clinical call.

CHI3L2 p.Ser57Pro

c.169T>C · VCV4002351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7398 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7398	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -4.5, phastCons 0.002
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.1 · 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 0.0267% East Asian · 12/44,876 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00112% 18/1,614,010 alleles · ultra-rare exomes 15/1,461,840 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Admixed American	0.00833%	12,003
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: CHI3L2
Protein: p.Ser57Pro
Coding: c.169T>C
MANE Select: NM_004000
Type: single nucleotide variant
Location: chr1:111230840 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.96 · 5 PDB
Residue 57: the gh18 domain; a β-strand

Full CHI3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHI3L2 p.Arg318Trp Benign ★★ same type
CHI3L2 p.Leu390= Benign ★★ same type
CHI3L2 p.Val184Ile Benign/Likely benign ★★ ⚠ same type
CHI3L2 p.Ala292Thr Uncertain significance ★ ⚠ same type
CHI3L2 p.Ala327Thr Uncertain significance ★ ⚠ same type
CHI3L2 p.Ala327Val Uncertain significance ★ ⚠ same type
CHI3L2 p.Ala64Thr Uncertain significance ★ ⚠ same type
CHI3L2 p.Arg385Gly 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/chi3l2-p-ser57pro (accessed [today's date]).

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