Is CHIT1 p.Lys253= (c.759G>A) pathogenic?

CHIT1 p.Lys253= (c.759G>A) is classified Conflicting classifications of pathogenicity in CHIT1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-23). Low-frequency (popmax 1.31%, afr); Associated with Chitotriosidase deficiency.

What condition is associated with CHIT1 p.Lys253= (c.759G>A)?

CHIT1 p.Lys253= (c.759G>A) is associated with Chitotriosidase deficiency (ClinVar).

How common is CHIT1 p.Lys253= (c.759G>A) in the general population?

CHIT1 p.Lys253= (c.759G>A) is low-frequency (popmax 1.31%, afr) (gnomAD).

CHIT1 p.Lys253=

c.759G>A · rs138767766 · VCV788174

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.31%, afr)

Conditions

Chitotriosidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.015	GERP -3.9, phastCons 0.8
Overall
CADD	2.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.31% African / African-American · 981/74,968 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.21%

Overall 0.0664% 1,070/1,612,298 alleles · low-frequency exomes 518/1,460,030 · genomes 552/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.31%	76
Remaining individualsnot grpmax-eligible	0.0722%	1,385
Admixed American	0.0467%	2,143
European (non-Finnish)	0.00136%	73,741

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.Lys253=
Coding: c.759G>A
MANE Select: NM_003465
dbSNP: rs138767766
Type: single nucleotide variant
Location: chr1:203219820 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 23 PDB
Residue 253: the gh18 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 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
CHIT1 p.Ala442Gly 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-lys253 (accessed [today's date]).

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