Is ACHE p.Arg52Ser (c.154C>A) pathogenic?

ACHE p.Arg52Ser (c.154C>A) is classified Uncertain significance in ACHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.2676); Very rare (popmax 0.00986%, nfe).

How common is ACHE p.Arg52Ser (c.154C>A) in the general population?

ACHE p.Arg52Ser (c.154C>A) is very rare (popmax 0.00986%, nfe) (gnomAD).

What do computational predictors say about ACHE p.Arg52Ser (c.154C>A)?

AlphaMissense predicts likely benign (score 0.2676) — an in-silico prediction, not a clinical call.

ACHE p.Arg52Ser

c.154C>A · rs375017123 · VCV2370792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00986%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2676	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 176 bp · p 0.25 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00986% European (non-Finnish) · 113/1,146,398 alleles

Filtering AF 0.00833% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00782%

Overall 0.00764% 118/1,544,484 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00986%	10,145
Remaining individualsnot grpmax-eligible	0.00337%	29,706
Admixed American	0.00201%	49,818
Finnishnot grpmax-eligible	0.0017%	58,980
African / African-American	0.00138%	72,566

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.Arg52Ser
Coding: c.154C>A
MANE Select: NM_000665
dbSNP: rs375017123
Type: single nucleotide variant
Location: chr7:100894079 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 93.04 · 81 PDB
Residue 52: a β-strand

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-arg52ser (accessed [today's date]).

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