Is CYP2A7 p.Leu135Pro (c.404T>C) pathogenic?

CYP2A7 p.Leu135Pro (c.404T>C) is classified Uncertain significance in CYP2A7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.6534); Very rare (popmax 8.49e-05%, nfe).

How common is CYP2A7 p.Leu135Pro (c.404T>C) in the general population?

CYP2A7 p.Leu135Pro (c.404T>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CYP2A7 p.Leu135Pro (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.6534) — an in-silico prediction, not a clinical call.

CYP2A7 p.Leu135Pro

c.404T>C · VCV3837825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6534	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -14.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	phastCons 0.94
Regional constraint	o/e 1.11	unconstrained · MANE · 5,674 bp · p 0.0087 · regional, not allelic
Overall
CADD	26.5	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

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,256 alleles

Overall 6.21e-05% 1/1,609,636 alleles · very rare exomes 1/1,459,280 · genomes 0/150,356 · joint denominator

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: CYP2A7
Protein: p.Leu135Pro
Coding: c.404T>C
MANE Select: NM_000764
Type: single nucleotide variant
Location: chr19:40880568 (GRCh38)
Gene constraint: LOEUF 1.158 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.63

Full CYP2A7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP2A7 p.Leu135Met Uncertain significance ★ ⚠ same residue
CYP2A7 p.Ala133Pro Benign ★★ same type
CYP2A7 p.Ala3= Benign ★★ same type
CYP2A7 p.Arg372His Benign ★★ same type
CYP2A7 p.Asn438Tyr Benign ★★ same type
CYP2A7 p.Gln265Arg Benign ★★ same type
CYP2A7 p.Ser153Ala Benign ★★ same type
CYP2A7 p.Ser397= Benign ★★ 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/cyp2a7-p-leu135pro (accessed [today's date]).

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