Is LIG4 p.Ser391del (c.1169GTA[1]) pathogenic?

LIG4 p.Ser391del (c.1169GTA[1]) is classified Uncertain significance in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-24). Very rare (popmax 0.004%, afr); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Ser391del (c.1169GTA[1])?

LIG4 p.Ser391del (c.1169GTA[1]) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Ser391del (c.1169GTA[1]) in the general population?

LIG4 p.Ser391del (c.1169GTA[1]) is very rare (popmax 0.004%, afr) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Ser391del

c.1169GTA[1] · rs775835184 · VCV2172210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

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 · substitutions only
Constraint at this position
Conservation	phyloP 4.2	GERP -3, phastCons 0.26
Overall
CADD	4.667	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,918 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00316% 51/1,613,288 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
European (non-Finnish)	0.0039%	25,650
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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.Ser391del
Coding: c.1169GTA[1]
MANE Select: NM_206937
dbSNP: rs775835184
Type: Microsatellite
Location: chr13:108210095 (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 391: 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.Ser391Gly Uncertain significance ★★ ⚠ 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
LIG4 p.Pro674fs Pathogenic ★ same condition
LIG4 p.Pro809fs 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-ser391del (accessed [today's date]).

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