Is CYP4F22 p.Arg451Pro (c.1352G>C) pathogenic?

CYP4F22 p.Arg451Pro (c.1352G>C) is classified Pathogenic in CYP4F22 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-04-23). AlphaMissense: likely pathogenic (0.9739); Very rare (popmax 0.00133%, afr); Associated with autosomal recessive congenital ichthyosis 5.

What condition is associated with CYP4F22 p.Arg451Pro (c.1352G>C)?

CYP4F22 p.Arg451Pro (c.1352G>C) is associated with autosomal recessive congenital ichthyosis 5 (ClinVar).

How common is CYP4F22 p.Arg451Pro (c.1352G>C) in the general population?

CYP4F22 p.Arg451Pro (c.1352G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Lamellar ichthyosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CYP4F22 p.Arg451Pro (c.1352G>C)?

AlphaMissense predicts likely pathogenic (score 0.9739) — an in-silico prediction, not a clinical call.

CYP4F22 p.Arg451Pro

c.1352G>C · rs144961059 · VCV560317

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive congenital ichthyosis 5

Computational evidence

Protein change
AlphaMissense	0.9739	likely pathogenic ✓ concordant with ClinVar · top 5% in CYP4F22
REVEL	0.961	strongly pathogenic-leaning
SaProt	LLR -16.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 2,309 bp · p 0.33 · regional, not allelic
Overall
CADD	34.0	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 0.00133% African / African-American · 1/75,020 alleles

Overall 6.84e-05% 1/1,461,876 alleles · very rare

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: CYP4F22
Protein: p.Arg451Pro
Coding: c.1352G>C
MANE Select: NM_173483
dbSNP: rs144961059
Type: single nucleotide variant
Location: chr19:15550690 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.59

Full CYP4F22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive congenital ichthyosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lamellar ichthyosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CYP4F22 p.Arg451Cys Pathogenic/Likely pathogenic ★★ same residue
CYP4F22 p.Arg451His Uncertain significance ★ ⚠ same residue
CYP4F22 p.Arg451Ser Uncertain significance ★ ⚠ same residue
CYP4F22 c.940-1G>A Likely pathogenic ★★ same condition
CYP4F22 p.Arg156Cys Pathogenic ★★ same condition
CYP4F22 p.Arg243Cys Pathogenic/Likely pathogenic ★★ same condition
CYP4F22 p.Arg243His Pathogenic ★★ same condition
CYP4F22 p.Arg326Ter Pathogenic ★★ same condition

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/cyp4f22-p-arg451pro (accessed [today's date]).

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