Is CPE p.Val437Ile (c.1309G>A) pathogenic?

CPE p.Val437Ile (c.1309G>A) is classified Conflicting classifications of pathogenicity in CPE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0913); Rare (popmax 0.104%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CPE p.Val437Ile (c.1309G>A)?

CPE p.Val437Ile (c.1309G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CPE p.Val437Ile (c.1309G>A) in the general population?

CPE p.Val437Ile (c.1309G>A) is rare (popmax 0.104%, nfe) (gnomAD).

What do computational predictors say about CPE p.Val437Ile (c.1309G>A)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

CPE p.Val437Ile

c.1309G>A · rs141075309 · VCV1394547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.104%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.59	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 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 118 kb · p 0.00025 · regional, not allelic
Overall
CADD	22.8	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 0.104% European (non-Finnish) · 1,223/1,179,274 alleles

Filtering AF 0.0988% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0969%

Overall 0.082% 1,323/1,612,870 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.112%	897
European (non-Finnish)grpmax	0.104%	964
Remaining individualsnot grpmax-eligible	0.056%	1,784
Admixed American	0.0267%	3,741
African / African-American	0.0174%	5,760
East Asian	0.00446%	22,422
Finnishnot grpmax-eligible	0.00156%	64,032

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val437Ile
Coding: c.1309G>A
MANE Select: NM_001873
dbSNP: rs141075309
Type: single nucleotide variant
Location: chr4:165495654 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 437: a UniProt-annotated variant site (in bdvs)

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.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
CPE p.Ala166Thr Uncertain significance ★ ⚠ 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-val437ile (accessed [today's date]).

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