Is CYP4F3 p.Ser229Arg (c.687T>G) pathogenic?

CYP4F3 p.Ser229Arg (c.687T>G) is classified Uncertain significance in CYP4F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.9162); Ultra-rare (popmax 0.0512%, eas).

How common is CYP4F3 p.Ser229Arg (c.687T>G) in the general population?

CYP4F3 p.Ser229Arg (c.687T>G) is ultra-rare (popmax 0.0512%, eas) (gnomAD).

What do computational predictors say about CYP4F3 p.Ser229Arg (c.687T>G)?

AlphaMissense predicts likely pathogenic (score 0.9162) — an in-silico prediction, not a clinical call.

CYP4F3 p.Ser229Arg

c.687T>G · rs202115280 · VCV2305594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9162	likely pathogenic · top 3% in CYP4F3
REVEL	0.598	indeterminate
SaProt	LLR -13.61	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 -4.3	GERP -2.4
Regional constraint	o/e 1.06	unconstrained · MANE · 18 kb · p 0.14 · regional, not allelic
Overall
CADD	21.1	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 0.0512% East Asian · 23/44,880 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00155% 25/1,614,154 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0512%	1,951
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Ser229Arg
Coding: c.687T>G
MANE Select: NM_000896
dbSNP: rs202115280
Type: single nucleotide variant
Location: chr19:15649952 (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-ser229arg (accessed [today's date]).

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