Is LIG4 p.Pro674fs (c.2019_2022del) pathogenic?

LIG4 p.Pro674fs (c.20192022del) is classified Pathogenic in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-24). Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Pro674fs (c.2019_2022del)?

LIG4 p.Pro674fs (c.2019_2022del) is associated with DNA ligase IV deficiency (ClinVar).

How is LIG4 syndrome inherited?

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

LIG4 p.Pro674fs

c.2019_2022del · VCV3647439

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 7.9	GERP 1.9, phastCons 1

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

Variant & gene context

Gene: LIG4
Protein: p.Pro674fs
Coding: c.2019_2022del
MANE Select: NM_206937
Type: Microsatellite
Location: chr13:108209247 (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 674: the brct 1 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.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
LIG4 p.Pro809fs Pathogenic ★ same condition
LIG4 p.Ser63fs Pathogenic ★ same condition
LIG4 p.Tyr548fs 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-pro674fs (accessed [today's date]).

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