Is CHI3L2 p.Ser240Arg (c.720C>A) pathogenic?

CHI3L2 p.Ser240Arg (c.720C>A) is classified Uncertain significance in CHI3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.3432); Rare (popmax 0.107%, amr).

How common is CHI3L2 p.Ser240Arg (c.720C>A) in the general population?

CHI3L2 p.Ser240Arg (c.720C>A) is rare (popmax 0.107%, amr) (gnomAD).

What do computational predictors say about CHI3L2 p.Ser240Arg (c.720C>A)?

AlphaMissense predicts ambiguous (score 0.3432) — an in-silico prediction, not a clinical call.

CHI3L2 p.Ser240Arg

c.720C>A · VCV4228084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3432 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3432	ambiguous
REVEL	0.042	moderately benign-leaning
SaProt	LLR -7.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -0.58
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.1 · regional, not allelic
Overall
CADD	12.82	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 0.107% Admixed American · 64/60,022 alleles

Filtering AF 0.0856% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.078%

Overall 0.0276% 445/1,614,198 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.107%	938
Remaining individualsnot grpmax-eligible	0.04%	2,500
European (non-Finnish)	0.0276%	3,620
South Asian	0.0198%	5,060
Middle Eastern	0.0165%	6,062
African / African-American	0.00666%	15,012
Finnishnot grpmax-eligible	0.00625%	16,008
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,890

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.Ser240Arg
Coding: c.720C>A
MANE Select: NM_004000
Type: single nucleotide variant
Location: chr1:111236138 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.96 · 5 PDB
Residue 240: the gh18 domain; an α-helix

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-ser240arg (accessed [today's date]).

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