Is CHAT p.Arg19Ile (c.56G>T) pathogenic?

CHAT p.Arg19Ile (c.56G>T) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-22). AlphaMissense: likely benign (0.1728); Very rare (popmax 0.00549%, afr).

How common is CHAT p.Arg19Ile (c.56G>T) in the general population?

CHAT p.Arg19Ile (c.56G>T) is very rare (popmax 0.00549%, afr) (gnomAD).

What do computational predictors say about CHAT p.Arg19Ile (c.56G>T)?

AlphaMissense predicts likely benign (score 0.1728) — an in-silico prediction, not a clinical call.

CHAT p.Arg19Ile

c.56G>T · VCV4907284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1728	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -3
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	12.86	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% African / African-American · 4/72,874 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.000323% 5/1,545,880 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00549%	18,218
European (non-Finnish)	8.74e-05%	1,144,580

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: CHAT
Protein: p.Arg19Ile
Coding: c.56G>T
MANE Select: NM_020549
Type: single nucleotide variant
Location: chr10:49614245 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB
Residue 19: the 'disordered' region

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

Similar variants

CHAT p.Arg19Gly Uncertain significance ★ ⚠ same residue
CHAT c.1282-2A>T Likely pathogenic ★★ same type
CHAT c.1840-9A>G Pathogenic/Likely pathogenic ★★ same type
CHAT c.698+1G>T Likely pathogenic ★★ same type
CHAT c.698+2T>C Likely pathogenic ★★ same type
CHAT p.Ala557Thr Pathogenic/Likely pathogenic ★★ same type
CHAT p.Arg151Ter Pathogenic/Likely pathogenic ★★ same type
CHAT p.Arg207Gly Likely pathogenic ★★ same type

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/chat-p-arg19ile (accessed [today's date]).

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