Is LIG4 p.Arg628fs (c.1880dup) pathogenic?

LIG4 p.Arg628fs (c.1880dup) is classified Pathogenic in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). Very rare (popmax 0.00133%, afr); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Arg628fs (c.1880dup)?

LIG4 p.Arg628fs (c.1880dup) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Arg628fs (c.1880dup) in the general population?

LIG4 p.Arg628fs (c.1880dup) is very rare (popmax 0.00133%, afr) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Arg628fs

c.1880dup · rs2501591208 · VCV2720977

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 0.19	GERP 0.14, phastCons 0.49

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,988 alleles

Overall 6.84e-05% 1/1,461,864 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.Arg628fs
Coding: c.1880dup
MANE Select: NM_206937
dbSNP: rs2501591208
Type: Duplication
Location: chr13:108209388 (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 628: 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.Arg628Gln Uncertain significance ★★ ⚠ same residue
LIG4 p.Arg628Trp Uncertain significance ★★ ⚠ same residue
LIG4 p.Arg628= Likely benign ★ same residue
LIG4 p.Ile36fs Pathogenic ★ same condition
LIG4 p.Ile84fs Pathogenic ★ same condition
LIG4 p.Leu418fs Pathogenic ★ same condition
LIG4 p.Leu810fs Pathogenic ★ same condition
LIG4 p.Met430fs 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-arg628fs (accessed [today's date]).

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