Is CYP4F3 p.Leu421Phe (c.1261C>T) pathogenic?

CYP4F3 p.Leu421Phe (c.1261C>T) is classified Uncertain significance in CYP4F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1823); Absent from gnomAD v4.1.

How common is CYP4F3 p.Leu421Phe (c.1261C>T) in the general population?

CYP4F3 p.Leu421Phe (c.1261C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYP4F3 p.Leu421Phe (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1823) — an in-silico prediction, not a clinical call.

CYP4F3 p.Leu421Phe

c.1261C>T · VCV4839441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1823 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1823	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.12	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 -20	GERP -3.7
Regional constraint	o/e 1.06	unconstrained · MANE · 18 kb · p 0.14 · regional, not allelic
Overall
CADD	8.528	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

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: CYP4F3
Protein: p.Leu421Phe
Coding: c.1261C>T
MANE Select: NM_000896
Type: single nucleotide variant
Location: chr19:15658502 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.04

Full CYP4F3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP4F3 c.1398-10C>T Benign ★★ same type
CYP4F3 p.Ile173= Likely benign ★★ same type
CYP4F3 p.Met191Val Benign ★★ same type
CYP4F3 p.Val270Ile Benign/Likely benign ★★ ⚠ same type
CYP4F3 p.Val398Ile Benign ★★ same type
CYP4F3 c.199-1688G>A Uncertain significance ★ same type
CYP4F3 c.199-1695A>T Uncertain significance ★ same type
CYP4F3 c.199-1709T>G 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/cyp4f3-p-leu421phe (accessed [today's date]).

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