Is ACHE p.Val147Ile (c.439G>A) pathogenic?

ACHE p.Val147Ile (c.439G>A) is classified Uncertain significance in ACHE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: likely benign (0.0728); Very rare (popmax 0.00475%, nfe).

How common is ACHE p.Val147Ile (c.439G>A) in the general population?

ACHE p.Val147Ile (c.439G>A) is very rare (popmax 0.00475%, nfe) (gnomAD).

What do computational predictors say about ACHE p.Val147Ile (c.439G>A)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

ACHE p.Val147Ile

c.439G>A · rs146564868 · VCV2591999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19
Regional constraint	o/e 0.63	unconstrained · MANE · 1,713 bp · p 7.6e-21 · regional, not allelic
Overall
CADD	12.14	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 0.00475% European (non-Finnish) · 56/1,180,004 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.0039% 63/1,613,724 alleles · very rare exomes 54/1,461,556 · genomes 9/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00475%	21,071
East Asian	0.00445%	22,451
Admixed American	0.00333%	29,995
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00133%	74,912

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.Val147Ile
Coding: c.439G>A
MANE Select: NM_000665
dbSNP: rs146564868
Type: single nucleotide variant
Location: chr7:100893794 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 93.04 · 81 PDB
Residue 147: 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-val147ile (accessed [today's date]).

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