Is CHAT p.Arg9Gly (c.25A>G) pathogenic?

CHAT p.Arg9Gly (c.25A>G) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2013-08-26). AlphaMissense: likely benign (0.0778); Ultra-rare (popmax 0.0327%, mid).

How common is CHAT p.Arg9Gly (c.25A>G) in the general population?

CHAT p.Arg9Gly (c.25A>G) is ultra-rare (popmax 0.0327%, mid) (gnomAD).

What do computational predictors say about CHAT p.Arg9Gly (c.25A>G)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

CHAT p.Arg9Gly

c.25A>G · rs587780314 · VCV128723

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0327%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -6.07	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 1.3	GERP -3.1, phastCons 0.16
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	6.304	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 0.0327% Middle Eastern · 1/3,056 alleles

Filtering AF 0.00521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00281% 26/925,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0327%	3,056
Admixed American	0.0155%	6,453
African / African-American	0.00777%	12,869
Ashkenazi Jewishnot grpmax-eligible	0.00507%	19,714
Remaining individualsnot grpmax-eligible	0.00251%	39,910
European (non-Finnish)	0.00236%	42,332
South Asian	0.00161%	62,174

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.Arg9Gly
Coding: c.25A>G
MANE Select: NM_020549
dbSNP: rs587780314
Type: single nucleotide variant
Location: chr10:49614214 (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 9: the 'disordered' region

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

Similar variants

CHAT p.Arg9Lys Uncertain significance ★ ⚠ same residue
CHAT p.Arg9= Likely benign ★ 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

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-arg9gly (accessed [today's date]).

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