Is CHIT1 p.Ala442= (c.1326G>A) pathogenic?

CHIT1 p.Ala442= (c.1326G>A) is classified Conflicting classifications of pathogenicity in CHIT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-19). Rare (popmax 0.328%, amr); Associated with Chitotriosidase deficiency.

What condition is associated with CHIT1 p.Ala442= (c.1326G>A)?

CHIT1 p.Ala442= (c.1326G>A) is associated with Chitotriosidase deficiency (ClinVar).

How common is CHIT1 p.Ala442= (c.1326G>A) in the general population?

CHIT1 p.Ala442= (c.1326G>A) is rare (popmax 0.328%, amr) (gnomAD).

CHIT1 p.Ala442=

c.1326G>A · rs186594769 · VCV769546

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.328%, amr)

Conditions

Chitotriosidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.5	GERP -3.7
Overall
CADD	8.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.328% Admixed American · 197/60,028 alleles

Filtering AF 0.291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.276%

Overall 0.0167% 270/1,614,164 alleles · rare exomes 251/1,461,824 · genomes 19/152,340 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.328%	305
South Asian	0.056%	1,786
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00446%	22,441
African / African-American	0.00266%	37,531
European (non-Finnish)	0.0011%	90,768

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: CHIT1
Protein: p.Ala442=
Coding: c.1326G>A
MANE Select: NM_003465
dbSNP: rs186594769
Type: single nucleotide variant
Location: chr1:203216964 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 23 PDB
Residue 442: a UniProt-annotated variant site (in); the chitin-binding type-2 domain

Full CHIT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Chitotriosidase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHIT1 p.Ala442Gly Benign ★★ same residue
CHIT1 p.Ala442Glu Uncertain significance ★ ⚠ same residue
CHIT1 p.Ala442Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CHIT1 c.-13G>A Uncertain significance ★★ same condition
CHIT1 c.*119C>T Uncertain significance ★★ same condition
CHIT1 p.Arg128His Uncertain significance ★★ ⚠ same condition
CHIT1 p.Arg432Trp Uncertain significance ★★ ⚠ same condition
CHIT1 p.Pro451Arg Uncertain significance ★★ ⚠ same condition

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/chit1-p-ala442 (accessed [today's date]).

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