Is CYP2E1 p.Val396Asp (c.1187T>A) pathogenic?

CYP2E1 p.Val396Asp (c.1187T>A) is classified Uncertain significance in CYP2E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.957); Absent from gnomAD v4.1.

How common is CYP2E1 p.Val396Asp (c.1187T>A) in the general population?

CYP2E1 p.Val396Asp (c.1187T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYP2E1 p.Val396Asp (c.1187T>A)?

AlphaMissense predicts likely pathogenic (score 0.957) — an in-silico prediction, not a clinical call.

CYP2E1 p.Val396Asp

c.1187T>A · VCV4236895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.957	likely pathogenic · top 4% in CYP2E1
REVEL	0.584	indeterminate
SaProt	LLR -13.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0067 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYP2E1
Protein: p.Val396Asp
Coding: c.1187T>A
MANE Select: NM_000773
Type: single nucleotide variant
Location: chr10:133537782 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.22 · 6 PDB
Residue 396: an α-helix

Full CYP2E1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP2E1 p.Val396Leu Likely benign ★ ⚠ same residue
CYP2E1 p.Asn204= Benign ★★ same type
CYP2E1 p.His457Leu Benign ★★ ⚠ same type
CYP2E1 p.Ile321= Benign ★★ same type
CYP2E1 p.Phe421= Benign ★★ same type
CYP2E1 p.Pro348= Benign ★★ same type
CYP2E1 p.Ser98= Benign ★★ same type
CYP2E1 p.Ala105Val 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/cyp2e1-p-val396asp (accessed [today's date]).

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