Is ACHE p.Pro135Ala (c.403C>G) pathogenic?

ACHE p.Pro135Ala (c.403C>G) is classified Likely benign in ACHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.1548); Rare (popmax 0.711%, mid).

How common is ACHE p.Pro135Ala (c.403C>G) in the general population?

ACHE p.Pro135Ala (c.403C>G) is rare (popmax 0.711%, mid) (gnomAD).

What do computational predictors say about ACHE p.Pro135Ala (c.403C>G)?

AlphaMissense predicts likely benign (score 0.1548) — an in-silico prediction, not a clinical call.

ACHE p.Pro135Ala

c.403C>G · rs17885778 · VCV780701

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1548 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.711%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1548	likely benign
REVEL	0.632	indeterminate
SaProt	LLR -11.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 1,713 bp · p 7.6e-21 · regional, not allelic
Overall
CADD	25.8	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 0.711% Middle Eastern · 43/6,050 alleles

Filtering AF 0.542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.483%

Overall 0.111% 1,793/1,612,722 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.711%	141
Ashkenazi Jewishnot grpmax-eligible	0.241%	415
South Asian	0.203%	491
Remaining individualsnot grpmax-eligible	0.171%	584
European (non-Finnish)	0.112%	890
Admixed American	0.0769%	1,301
African / African-American	0.02%	5,001
East Asian	0.00223%	44,870

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.Pro135Ala
Coding: c.403C>G
MANE Select: NM_000665
dbSNP: rs17885778
Type: single nucleotide variant
Location: chr7:100893830 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 93.04 · 81 PDB
Residue 135: a UniProt-annotated variant site (in); a β-strand

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

Similar variants

ACHE p.Pro135Arg Uncertain significance ★ ⚠ same residue
ACHE p.Arg34Gln Benign ★★ same type
ACHE p.Glu344= Benign/Likely benign ★★ same type
ACHE p.Gly89Glu 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-pro135ala (accessed [today's date]).

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