Is ACHE p.Arg44Cys (c.130C>T) pathogenic?

ACHE p.Arg44Cys (c.130C>T) is classified Uncertain significance in ACHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1813); Ultra-rare (popmax 0.0182%, mid).

How common is ACHE p.Arg44Cys (c.130C>T) in the general population?

ACHE p.Arg44Cys (c.130C>T) is ultra-rare (popmax 0.0182%, mid) (gnomAD).

What do computational predictors say about ACHE p.Arg44Cys (c.130C>T)?

AlphaMissense predicts likely benign (score 0.1813) — an in-silico prediction, not a clinical call.

ACHE p.Arg44Cys

c.130C>T · VCV4215469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1813	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -13.74	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.3	phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 176 bp · p 0.25 · regional, not allelic
Overall
CADD	24.0	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 0.0182% Middle Eastern · 1/5,492 alleles

Filtering AF 0.00331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00298%

Overall 0.00376% 57/1,514,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0182%	5,492
South Asian	0.00645%	15,495
European (non-Finnish)	0.00432%	23,128
Remaining individualsnot grpmax-eligible	0.00343%	29,146

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: ACHE
Protein: p.Arg44Cys
Coding: c.130C>T
MANE Select: NM_000665
Type: single nucleotide variant
Location: chr7:100894103 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 93.04 · 81 PDB

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

Similar variants

ACHE p.Arg34Gln Benign ★★ same type
ACHE p.Glu344= Benign/Likely benign ★★ same type
ACHE p.Gly89Glu Benign ★★ ⚠ same type
ACHE p.Pro135Ala Likely benign ★★ ⚠ same type
ACHE p.Pro441= Likely benign ★★ same type
ACHE p.Thr269= Benign/Likely benign ★★ same type
ACHE p.Ala14Thr Uncertain significance ★ ⚠ same type
ACHE p.Ala256Thr Uncertain significance ★ ⚠ 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/ache-p-arg44cys (accessed [today's date]).

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