Is CHAT p.Arg545Ser (c.1635G>T) pathogenic?

CHAT p.Arg545Ser (c.1635G>T) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.8698); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Arg545Ser (c.1635G>T)?

CHAT p.Arg545Ser (c.1635G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHAT p.Arg545Ser (c.1635G>T) in the general population?

CHAT p.Arg545Ser (c.1635G>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CHAT p.Arg545Ser (c.1635G>T)?

AlphaMissense predicts likely pathogenic (score 0.8698) — an in-silico prediction, not a clinical call.

CHAT p.Arg545Ser

c.1635G>T · VCV3266800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8698	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -0.95, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	24.4	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 0.00329% South Asian · 3/91,076 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00136% 22/1,613,968 alleles · very rare exomes 20/1,461,846 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
European (non-Finnish)	0.00161%	62,106

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.Arg545Ser
Coding: c.1635G>T
MANE Select: NM_020549
Type: single nucleotide variant
Location: chr10:49655095 (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 545: 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

Similar variants

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
CHAT p.Arg484Trp Uncertain significance ★★ ⚠ same condition
CHAT p.Arg628Trp 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-arg545ser (accessed [today's date]).

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