Is CHAT p.Pro135Ser (c.403C>T) pathogenic?

CHAT p.Pro135Ser (c.403C>T) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-01). AlphaMissense: ambiguous (0.5017); Ultra-rare (popmax 0.0186%, mid); Associated with Gait disturbance.

What condition is associated with CHAT p.Pro135Ser (c.403C>T)?

CHAT p.Pro135Ser (c.403C>T) is associated with Gait disturbance (ClinVar).

How common is CHAT p.Pro135Ser (c.403C>T) in the general population?

CHAT p.Pro135Ser (c.403C>T) is ultra-rare (popmax 0.0186%, mid) (gnomAD).

What do computational predictors say about CHAT p.Pro135Ser (c.403C>T)?

AlphaMissense predicts ambiguous (score 0.5017) — an in-silico prediction, not a clinical call.

CHAT p.Pro135Ser

c.403C>T · rs1554802473 · VCV523530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5017 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Gait disturbance

Computational evidence

Protein change
AlphaMissense	0.5017	ambiguous
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -12.45	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	25.2	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 0.0186% Middle Eastern · 1/5,376 alleles

Overall 6.85e-05% 1/1,459,994 alleles · ultra-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.Pro135Ser
Coding: c.403C>T
MANE Select: NM_020549
dbSNP: rs1554802473
Type: single nucleotide variant
Location: chr10:49619740 (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 135: an α-helix

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

Disease context

Gait disturbance — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHAT p.Pro135= Likely benign ★ same residue
CHAT c.1282-2A>T Likely pathogenic ★★ same type
CHAT c.1840-9A>G Pathogenic/Likely pathogenic ★★ same type
CHAT c.698+1G>T Likely pathogenic ★★ same type
CHAT c.698+2T>C Likely pathogenic ★★ same type
CHAT p.Ala557Thr Pathogenic/Likely pathogenic ★★ same type
CHAT p.Arg151Ter Pathogenic/Likely pathogenic ★★ same type
CHAT p.Arg207Gly Likely pathogenic ★★ same type

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-pro135ser (accessed [today's date]).

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