Is CHAT p.Ser694Cys (c.2081C>G) pathogenic?

CHAT p.Ser694Cys (c.2081C>G) is classified Pathogenic in CHAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-26). AlphaMissense: ambiguous (0.3941); Very rare (popmax 8.47e-05%, nfe); Associated with Gastroesophageal reflux.

What condition is associated with CHAT p.Ser694Cys (c.2081C>G)?

CHAT p.Ser694Cys (c.2081C>G) is associated with Gastroesophageal reflux, aspiration pneumonia, flatfoot (ClinVar).

How common is CHAT p.Ser694Cys (c.2081C>G) in the general population?

CHAT p.Ser694Cys (c.2081C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Ser694Cys (c.2081C>G)?

AlphaMissense predicts ambiguous (score 0.3941) — an in-silico prediction, not a clinical call.

CHAT p.Ser694Cys

c.2081C>G · rs201439531 · VCV523529

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Gastroesophageal reflux

Computational evidence

Protein change
AlphaMissense	0.3941	ambiguous
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -9.12	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	28.5	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 8.47e-05% European (non-Finnish) · 1/1,180,052 alleles

Overall 0.000657% 1/152,242 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.Ser694Cys
Coding: c.2081C>G
MANE Select: NM_020549
dbSNP: rs201439531
Type: single nucleotide variant
Location: chr10:49664880 (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 694: a β-strand

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

Disease context

Gastroesophageal reflux — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aspiration pneumonia flatfoot lactic acidosis 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-ser694cys (accessed [today's date]).

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