Is CPE p.Ala166Val (c.497C>T) pathogenic?

CPE p.Ala166Val (c.497C>T) is classified Uncertain significance in CPE (ClinVar, Single submitter, 2 submitters; last evaluated 2023-11-15). AlphaMissense: likely benign (0.3261); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with CPE p.Ala166Val (c.497C>T)?

CPE p.Ala166Val (c.497C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CPE p.Ala166Val (c.497C>T) in the general population?

CPE p.Ala166Val (c.497C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about CPE p.Ala166Val (c.497C>T)?

AlphaMissense predicts likely benign (score 0.3261) — an in-silico prediction, not a clinical call.

CPE p.Ala166Val

c.497C>T · rs780735154 · VCV3029146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3261 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3261	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -7.87	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 118 kb · p 0.00025 · regional, not allelic
Overall
CADD	23.1	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 0.016% African / African-American · 12/74,812 alleles

Filtering AF 0.00923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00723%

Overall 0.000932% 15/1,608,634 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,234
Remaining individualsnot grpmax-eligible	0.00161%	62,264
South Asian	0.00111%	90,442
European (non-Finnish)	8.5e-05%	1,176,675

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: CPE
Protein: p.Ala166Val
Coding: c.497C>T
MANE Select: NM_001873
dbSNP: rs780735154
Type: single nucleotide variant
Location: chr4:165464579 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 166: a UniProt-annotated variant site (in bdvs); the peptidase m14 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPE p.Ala166Thr Uncertain significance ★ ⚠ same residue
CPE p.Arg262Trp Uncertain significance ★★ ⚠ same condition
CPE p.Arg297Trp Uncertain significance ★★ ⚠ same condition
CPE p.Asp251Gly Uncertain significance ★★ ⚠ same condition
CPE p.Asp304Ala Uncertain significance ★★ ⚠ same condition
CPE p.Trp21Cys Uncertain significance ★★ ⚠ same condition
CPE p.Gln384= Likely benign ★★ same condition
CPE p.Gln384Ter Pathogenic ★ same condition

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/cpe-p-ala166val (accessed [today's date]).

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