Is LIG4 p.Pro491= (c.1473C>G) pathogenic?

LIG4 p.Pro491= (c.1473C>G) is classified Benign/Likely benign in LIG4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-11). Rare (popmax 0.232%, eas); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Pro491= (c.1473C>G)?

LIG4 p.Pro491= (c.1473C>G) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Pro491= (c.1473C>G) in the general population?

LIG4 p.Pro491= (c.1473C>G) is rare (popmax 0.232%, eas) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Pro491=

c.1473C>G · rs189319839 · VCV211372

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.232%, eas)

Conditions

DNA ligase IV deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -0.21
Overall
CADD	3.296	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.232% East Asian · 104/44,876 alleles

Filtering AF 0.196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.182%

Overall 0.007% 113/1,613,994 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.232%	431
Remaining individualsnot grpmax-eligible	0.0144%	6,945

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.Pro491=
Coding: c.1473C>G
MANE Select: NM_206937
dbSNP: rs189319839
Type: single nucleotide variant
Location: chr13:108209796 (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 491: an α-helix

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.Arg278His Pathogenic ★★ same condition
LIG4 p.Arg278Leu Pathogenic ★★ same condition
LIG4 p.Arg293Ter Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Arg580Ter Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Arg814Ter Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Gln74Ter Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Gln773Ter Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.His282Arg Likely 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-pro491 (accessed [today's date]).

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