Is CHIT1 p.Ser122= (c.366G>A) pathogenic?

CHIT1 p.Ser122= (c.366G>A) is classified Conflicting classifications of pathogenicity in CHIT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-08). Ultra-rare (popmax 0.0111%, eas); Associated with Chitotriosidase deficiency.

What condition is associated with CHIT1 p.Ser122= (c.366G>A)?

CHIT1 p.Ser122= (c.366G>A) is associated with Chitotriosidase deficiency (ClinVar).

How common is CHIT1 p.Ser122= (c.366G>A) in the general population?

CHIT1 p.Ser122= (c.366G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

CHIT1 p.Ser122=

c.366G>A · rs367910344 · VCV294933

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

Chitotriosidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.27	acceptor loss, 9 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -5.3	GERP -3.9
Overall
CADD	4.524	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,898 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00731% 118/1,614,066 alleles · ultra-rare exomes 109/1,461,892 · genomes 9/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,980
European (non-Finnish)	0.00873%	11,457
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.00401%	24,969
South Asian	0.00329%	30,363
Admixed American	0.00167%	60,008

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.Ser122=
Coding: c.366G>A
MANE Select: NM_003465
dbSNP: rs367910344
Type: single nucleotide variant
Location: chr1:203223609 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 23 PDB
Residue 122: the gh18 domain; an α-helix

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.Ser122Leu 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
CHIT1 c.25+8G>T Likely benign ★★ same condition
CHIT1 c.258-6T>C Benign ★★ 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-ser122 (accessed [today's date]).

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