Is CHIT1 p.Ser226Arg (c.678C>A) pathogenic?

CHIT1 p.Ser226Arg (c.678C>A) is classified Conflicting classifications of pathogenicity in CHIT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.9536); Ultra-rare (popmax 0.0883%, amr); Associated with Chitotriosidase deficiency.

What condition is associated with CHIT1 p.Ser226Arg (c.678C>A)?

CHIT1 p.Ser226Arg (c.678C>A) is associated with Chitotriosidase deficiency (ClinVar).

How common is CHIT1 p.Ser226Arg (c.678C>A) in the general population?

CHIT1 p.Ser226Arg (c.678C>A) is ultra-rare (popmax 0.0883%, amr) (gnomAD).

What do computational predictors say about CHIT1 p.Ser226Arg (c.678C>A)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

CHIT1 p.Ser226Arg

c.678C>A · rs193156676 · VCV1551786

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0883%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Chitotriosidase deficiency

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic · top 1% in CHIT1
REVEL	0.487	indeterminate
SaProt	LLR -14.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -2.8, phastCons 0.93
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.56 · regional, not allelic
Overall
CADD	22.7	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 0.0883% Admixed American · 53/60,026 alleles

Filtering AF 0.0693% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0625%

Overall 0.00335% 54/1,614,212 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0883%	1,133
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Ser226Arg
Coding: c.678C>A
MANE Select: NM_003465
dbSNP: rs193156676
Type: single nucleotide variant
Location: chr1:203222253 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 23 PDB
Residue 226: 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-ser226arg (accessed [today's date]).

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