Is CHAT p.Arg66Cys (c.196C>T) pathogenic?

CHAT p.Arg66Cys (c.196C>T) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.1305); Very rare (popmax 0.00119%, sas); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Arg66Cys (c.196C>T)?

CHAT p.Arg66Cys (c.196C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHAT p.Arg66Cys (c.196C>T) in the general population?

CHAT p.Arg66Cys (c.196C>T) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about CHAT p.Arg66Cys (c.196C>T)?

AlphaMissense predicts likely benign (score 0.1305) — an in-silico prediction, not a clinical call.

CHAT p.Arg66Cys

c.196C>T · VCV4002049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1305 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1305	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -7.87	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 0.34	GERP -2.2, phastCons 0.38
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	21.0	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 0.00119% South Asian · 1/83,816 alleles

Overall 7.19e-05% 1/1,391,620 alleles · very rare

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.Arg66Cys
Coding: c.196C>T
MANE Select: NM_020549
Type: single nucleotide variant
Location: chr10:49614385 (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 66: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHAT p.Arg66Ser Uncertain significance ★ ⚠ same residue
CHAT p.Arg66= Likely benign ★ same residue
CHAT p.Ala479Thr Uncertain significance ★★ ⚠ same condition
CHAT p.Ala579Thr Uncertain significance ★★ ⚠ same condition
CHAT p.Ala680Val Uncertain significance ★★ ⚠ same condition
CHAT p.Arg28Ser Uncertain significance ★★ ⚠ same condition
CHAT p.Arg383Pro Uncertain significance ★★ ⚠ same condition
CHAT p.Arg470Gln Uncertain significance ★★ ⚠ 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/chat-p-arg66cys (accessed [today's date]).

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