Is CYP4F8 p.Phe124Leu (c.372C>A) pathogenic?

CYP4F8 p.Phe124Leu (c.372C>A) is classified Uncertain significance in CYP4F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.7261); Rare (popmax 0.567%, afr).

How common is CYP4F8 p.Phe124Leu (c.372C>A) in the general population?

CYP4F8 p.Phe124Leu (c.372C>A) is rare (popmax 0.567%, afr) (gnomAD).

What do computational predictors say about CYP4F8 p.Phe124Leu (c.372C>A)?

AlphaMissense predicts likely pathogenic (score 0.7261) — an in-silico prediction, not a clinical call.

CYP4F8 p.Phe124Leu

c.372C>A · VCV4237109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7261 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.567%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7261	likely pathogenic · top 10% in CYP4F8
REVEL	0.087	moderately benign-leaning
SaProt	LLR -4.76	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.34	acceptor loss · deltas
Pangolin	Δ0.33	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.42	phastCons 0.009
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.93 · regional, not allelic
Overall
CADD	18.59	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 0.567% African / African-American · 426/75,072 alleles

Filtering AF 0.523% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.505%

Overall 0.0284% 458/1,614,214 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.567%	176
Admixed American	0.0283%	3,531
Remaining individualsnot grpmax-eligible	0.024%	4,167

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: CYP4F8
Protein: p.Phe124Leu
Coding: c.372C>A
MANE Select: NM_007253
Type: single nucleotide variant
Location: chr19:15619518 (GRCh38)
Gene constraint: LOEUF 1.232 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.45

Full CYP4F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP4F8 p.Ala269Val Uncertain significance ★ ⚠ same type
CYP4F8 p.Ala40Asp Uncertain significance ★ ⚠ same type
CYP4F8 p.Arg108Gln Uncertain significance ★ ⚠ same type
CYP4F8 p.Arg145Ile Uncertain significance ★ ⚠ same type
CYP4F8 p.Arg241Gln Uncertain significance ★ ⚠ same type
CYP4F8 p.Arg33His Uncertain significance ★ ⚠ same type
CYP4F8 p.Arg46Cys Uncertain significance ★ ⚠ same type
CYP4F8 p.Arg46His 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/cyp4f8-p-phe124leu (accessed [today's date]).

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