Is CHIT1 p.Ala59Pro (c.175G>C) pathogenic?

CHIT1 p.Ala59Pro (c.175G>C) is classified Benign in CHIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). AlphaMissense: likely pathogenic (0.576); Very rare (popmax 0.00133%, afr); Associated with Chitotriosidase deficiency.

What condition is associated with CHIT1 p.Ala59Pro (c.175G>C)?

CHIT1 p.Ala59Pro (c.175G>C) is associated with Chitotriosidase deficiency (ClinVar).

How common is CHIT1 p.Ala59Pro (c.175G>C) in the general population?

CHIT1 p.Ala59Pro (c.175G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CHIT1 p.Ala59Pro (c.175G>C)?

AlphaMissense predicts likely pathogenic (score 0.576) — an in-silico prediction, not a clinical call.

CHIT1 p.Ala59Pro

c.175G>C · VCV3662620

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Chitotriosidase deficiency

Computational evidence

Protein change
AlphaMissense	0.576	likely pathogenic
REVEL	0.234	benign-leaning
SaProt	LLR -14.93	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 1.7	GERP 0.9, phastCons 0.92
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.56 · regional, not allelic
Overall
CADD	22.1	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 0.00133% African / African-American · 1/74,914 alleles

Overall 6.2e-05% 1/1,614,020 alleles · very rare exomes 0/1,461,892 · genomes 1/152,128 · joint denominator

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.Ala59Pro
Coding: c.175G>C
MANE Select: NM_003465
Type: single nucleotide variant
Location: chr1:203225751 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 23 PDB
Residue 59: the gh18 domain; a β-strand

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.Ala59Thr 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-ala59pro (accessed [today's date]).

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