Is CHAT p.Val318Ala (c.953T>C) pathogenic?

CHAT p.Val318Ala (c.953T>C) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: ambiguous (0.5079); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Val318Ala (c.953T>C)?

CHAT p.Val318Ala (c.953T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CHAT p.Val318Ala (c.953T>C) in the general population?

CHAT p.Val318Ala (c.953T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Val318Ala (c.953T>C)?

AlphaMissense predicts ambiguous (score 0.5079) — an in-silico prediction, not a clinical call.

CHAT p.Val318Ala

c.953T>C · rs2496361907 · VCV3144055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5079 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5079	ambiguous
REVEL	0.635	indeterminate
SaProt	LLR -6.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	26.0	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) · 1/1,179,962 alleles

Overall 6.84e-05% 1/1,461,794 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.Val318Ala
Coding: c.953T>C
MANE Select: NM_020549
dbSNP: rs2496361907
Type: single nucleotide variant
Location: chr10:49627627 (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 318: a β-strand

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-val318ala (accessed [today's date]).

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