Is CYP4F3 p.Arg400His (c.1199G>A) pathogenic?

CYP4F3 p.Arg400His (c.1199G>A) is classified Uncertain significance in CYP4F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.4187); Very rare (popmax 0.00666%, amr).

How common is CYP4F3 p.Arg400His (c.1199G>A) in the general population?

CYP4F3 p.Arg400His (c.1199G>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about CYP4F3 p.Arg400His (c.1199G>A)?

AlphaMissense predicts ambiguous (score 0.4187) — an in-silico prediction, not a clinical call.

CYP4F3 p.Arg400His

c.1199G>A · VCV4658202

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4187	ambiguous
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 18 kb · p 0.14 · regional, not allelic
Overall
CADD	26.2	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 0.00666% Admixed American · 4/60,030 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00041% 6/1,461,858 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,008
African / African-American	0.00133%	75,014
European (non-Finnish)	8.47e-05%	1,180,013

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: CYP4F3
Protein: p.Arg400His
Coding: c.1199G>A
MANE Select: NM_000896
Type: single nucleotide variant
Location: chr19:15658347 (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-arg400his (accessed [today's date]).

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