Is CYP4F22 p.Phe334Ser (c.1001T>C) pathogenic?

CYP4F22 p.Phe334Ser (c.1001T>C) is classified Uncertain significance in CYP4F22 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9725); Absent from gnomAD v4.1; Associated with autosomal recessive congenital ichthyosis 5.

What condition is associated with CYP4F22 p.Phe334Ser (c.1001T>C)?

CYP4F22 p.Phe334Ser (c.1001T>C) is associated with autosomal recessive congenital ichthyosis 5 (ClinVar).

How common is CYP4F22 p.Phe334Ser (c.1001T>C) in the general population?

CYP4F22 p.Phe334Ser (c.1001T>C) is absent from gnomAD v4.1 (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.Phe334Ser (c.1001T>C)?

AlphaMissense predicts likely pathogenic (score 0.9725) — an in-silico prediction, not a clinical call.

CYP4F22 p.Phe334Ser

c.1001T>C · rs2513156213 · VCV2585185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9725 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive congenital ichthyosis 5

Computational evidence

Protein change
AlphaMissense	0.9725	likely pathogenic · top 5% in CYP4F22
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -13.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 19 kb · p 0.2 · regional, not allelic
Overall
CADD	32.0	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

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: CYP4F22
Protein: p.Phe334Ser
Coding: c.1001T>C
MANE Select: NM_173483
dbSNP: rs2513156213
Type: single nucleotide variant
Location: chr19:15544032 (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 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
CYP4F22 p.Arg362Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CYP4F22 p.Arg362Ter Pathogenic ★★ same condition
CYP4F22 p.Arg372Trp Likely 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-phe334ser (accessed [today's date]).

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