Is CHAT p.Val304Ile (c.910G>A) pathogenic?

CHAT p.Val304Ile (c.910G>A) is classified Likely benign in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-16). AlphaMissense: likely benign (0.0708); Rare (popmax 0.138%, eas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Val304Ile (c.910G>A)?

CHAT p.Val304Ile (c.910G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Val304Ile (c.910G>A) in the general population?

CHAT p.Val304Ile (c.910G>A) is rare (popmax 0.138%, eas) (gnomAD).

What do computational predictors say about CHAT p.Val304Ile (c.910G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

CHAT p.Val304Ile

c.910G>A · rs116362950 · VCV978543

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.138%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -4.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -3.1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	0.552	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 0.138% East Asian · 60/43,384 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.1%

Overall 0.00563% 89/1,580,870 alleles · rare exomes 82/1,428,532 · genomes 7/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.138%	723
Middle Eastern	0.0166%	6,026
South Asian	0.0127%	7,895
Admixed American	0.00546%	18,307
Remaining individualsnot grpmax-eligible	0.00326%	30,649
African / African-American	0.00269%	37,186
Finnishnot grpmax-eligible	0.00162%	61,768
European (non-Finnish)	0.000774%	129,154

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.Val304Ile
Coding: c.910G>A
MANE Select: NM_020549
dbSNP: rs116362950
Type: single nucleotide variant
Location: chr10:49625630 (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 304: a β-strand

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

Disease context

congenital myasthenic syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-val304ile (accessed [today's date]).

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