Is CHAT p.Ile165Thr (c.494T>C) pathogenic?

CHAT p.Ile165Thr (c.494T>C) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1208); Ultra-rare (popmax 0.056%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Ile165Thr (c.494T>C)?

CHAT p.Ile165Thr (c.494T>C) is associated with Inborn genetic diseases, congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Ile165Thr (c.494T>C) in the general population?

CHAT p.Ile165Thr (c.494T>C) is ultra-rare (popmax 0.056%, afr) (gnomAD).

What do computational predictors say about CHAT p.Ile165Thr (c.494T>C)?

AlphaMissense predicts likely benign (score 0.1208) — an in-silico prediction, not a clinical call.

CHAT p.Ile165Thr

c.494T>C · rs148155075 · VCV1099987

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1208 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1208	likely benign
REVEL	0.623	indeterminate
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	23.5	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 0.056% African / African-American · 42/75,038 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00304% 49/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.056%	1,787
Admixed American	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0032%	31,249
European (non-Finnish)	0.000254%	393,317

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.Ile165Thr
Coding: c.494T>C
MANE Select: NM_020549
dbSNP: rs148155075
Type: single nucleotide variant
Location: chr10:49619831 (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 165: an α-helix

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

Also linked: congenital myasthenic syndrome 6

Similar variants

CHAT c.1282-2A>T Likely pathogenic ★★ same condition
CHAT c.1840-9A>G Pathogenic/Likely pathogenic ★★ same condition
CHAT c.698+1G>T Likely pathogenic ★★ same condition
CHAT c.698+2T>C Likely pathogenic ★★ same condition
CHAT p.Ala557Thr Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg151Ter Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg207Gly Likely pathogenic ★★ same condition
CHAT p.Arg207His Pathogenic/Likely pathogenic ★★ ⚠ 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-ile165thr (accessed [today's date]).

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