Is LIG4 p.Pro528fs (c.1583del) pathogenic?

LIG4 p.Pro528fs (c.1583del) is classified Pathogenic in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-27). Very rare (popmax 0.000593%, nfe); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Pro528fs (c.1583del)?

LIG4 p.Pro528fs (c.1583del) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Pro528fs (c.1583del) in the general population?

LIG4 p.Pro528fs (c.1583del) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Pro528fs

c.1583del · rs1307623377 · VCV2896057

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

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 0.23	GERP -3.6, phastCons 0.31
Overall
CADD	33.0	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 0.000593% European (non-Finnish) · 7/1,180,018 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,978 alleles · very rare exomes 6/1,461,860 · genomes 1/152,118 · joint denominator

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.Pro528fs
Coding: c.1583del
MANE Select: NM_206937
dbSNP: rs1307623377
Type: Deletion
Location: chr13:108209686 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.44 · 32 PDB

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.Asn294fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Gln200fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Glu582fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.His862fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Ile584fs Pathogenic ★★ same condition
LIG4 p.Leu242fs Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Lys424fs Pathogenic ★★ same condition
LIG4 p.Lys635fs 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-pro528fs (accessed [today's date]).

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