Is DDB1 p.Ile558Phe (c.1672A>T) pathogenic?

DDB1 p.Ile558Phe (c.1672A>T) is classified Uncertain significance in DDB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-07). AlphaMissense: likely pathogenic (0.8652); Absent from gnomAD v4.1; Associated with White-Kernohan syndrome.

What condition is associated with DDB1 p.Ile558Phe (c.1672A>T)?

DDB1 p.Ile558Phe (c.1672A>T) is associated with White-Kernohan syndrome (ClinVar).

How common is DDB1 p.Ile558Phe (c.1672A>T) in the general population?

DDB1 p.Ile558Phe (c.1672A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DDB1 p.Ile558Phe (c.1672A>T)?

AlphaMissense predicts likely pathogenic (score 0.8652) — an in-silico prediction, not a clinical call.

DDB1 p.Ile558Phe

c.1672A>T · rs1468435299 · VCV2234913

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8652 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

White-Kernohan syndrome

Computational evidence

Protein change
AlphaMissense	0.8652	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -12.43	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 7,478 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	23.8	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

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: DDB1
Protein: p.Ile558Phe
Coding: c.1672A>T
MANE Select: NM_001923
dbSNP: rs1468435299
Type: single nucleotide variant
Location: chr11:61314128 (GRCh38)
Gene constraint: LOEUF 0.195 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 219 PDB
Residue 558: a β-strand; the 'interaction with cdt1' region; the 'wd repeat beta-propeller b; interaction with cul4a' region

Full DDB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

White-Kernohan syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DDB1 p.Ile558Val Uncertain significance ★ ⚠ same residue
DDB1 p.Arg188Trp Pathogenic/Likely pathogenic ★★ same condition
DDB1 p.Ile793Thr Uncertain significance ★★ ⚠ same condition
DDB1 p.Arg188Gln Pathogenic ★ same condition
DDB1 p.Glu213Lys Likely pathogenic ★ same condition
DDB1 p.Glu785Lys Likely pathogenic ★ same condition
DDB1 p.Ala968Ser Uncertain significance ★ ⚠ same condition
DDB1 p.Arg158Cys Uncertain significance ★ ⚠ 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/ddb1-p-ile558phe (accessed [today's date]).

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