Is ACHE p.Val460Ile (c.1378G>A) pathogenic?

ACHE p.Val460Ile (c.1378G>A) is classified Likely benign in ACHE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-10). AlphaMissense: likely benign (0.0644); Ultra-rare (popmax 0.0218%, amr).

How common is ACHE p.Val460Ile (c.1378G>A) in the general population?

ACHE p.Val460Ile (c.1378G>A) is ultra-rare (popmax 0.0218%, amr) (gnomAD).

What do computational predictors say about ACHE p.Val460Ile (c.1378G>A)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

ACHE p.Val460Ile

c.1378G>A · rs546907479 · VCV2358297

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -9.76	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 -5.4
Regional constraint	o/e 0.63	unconstrained · MANE · 1,713 bp · p 7.6e-21 · regional, not allelic
Overall
CADD	1.198	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 0.0218% Admixed American · 13/59,594 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00737% 118/1,601,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0218%	4,584
African / African-American	0.0174%	5,746
East Asian	0.0135%	7,413
Remaining individualsnot grpmax-eligible	0.00808%	12,372
European (non-Finnish)	0.00675%	14,815
South Asian	0.00221%	45,266

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.Val460Ile
Coding: c.1378G>A
MANE Select: NM_000665
dbSNP: rs546907479
Type: single nucleotide variant
Location: chr7:100892509 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 93.04 · 81 PDB
Residue 460: a disulfide bond; 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-val460ile (accessed [today's date]).

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