Is LIG4 p.Pro809fs (c.2426_2430del) pathogenic?

LIG4 p.Pro809fs (c.24262430del) is classified Pathogenic in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-28). Very rare (popmax 0.000657%); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Pro809fs (c.2426_2430del)?

LIG4 p.Pro809fs (c.2426_2430del) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Pro809fs (c.2426_2430del) in the general population?

LIG4 p.Pro809fs (c.2426_2430del) is very rare (popmax 0.000657%) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Pro809fs

c.2426_2430del · rs1878227240 · VCV2841622

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Conditions

DNA ligase IV deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -1, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000657%

Overall 0.000657% 1/152,162 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: LIG4
Protein: p.Pro809fs
Coding: c.2426_2430del
MANE Select: NM_206937
dbSNP: rs1878227240
Type: Microsatellite
Location: chr13:108208839 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.44 · 32 PDB
Residue 809: an α-helix; the brct 2 domain; a UniProt-annotated variant site (in lig4s)

Full LIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DNA ligase IV deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For LIG4 syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LIG4 p.Pro809Ala Uncertain significance ★★ ⚠ same residue
LIG4 p.Pro809Leu Uncertain significance ★★ ⚠ same residue
LIG4 p.Pro809= Likely benign ★ same residue
LIG4 p.Arg505fs Pathogenic ★★ same condition
LIG4 p.Leu382fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Ser267fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Arg880del Uncertain significance ★★ same condition
LIG4 p.Arg79fs 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/lig4-p-pro809fs (accessed [today's date]).

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