Is LIG4 p.Arg278= (c.834T>C) pathogenic?

LIG4 p.Arg278= (c.834T>C) is classified Likely benign in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-11). Ultra-rare (popmax 0.0133%, afr); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Arg278= (c.834T>C)?

LIG4 p.Arg278= (c.834T>C) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Arg278= (c.834T>C) in the general population?

LIG4 p.Arg278= (c.834T>C) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Arg278=

c.834T>C · rs375022046 · VCV1125298

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, 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 · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -5.2
Overall
CADD	0.636	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,932 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00062% 10/1,613,398 alleles · ultra-rare exomes 5/1,461,170 · genomes 5/152,228 · 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.Arg278=
Coding: c.834T>C
MANE Select: NM_206937
dbSNP: rs375022046
Type: single nucleotide variant
Location: chr13:108210435 (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 278: a UniProt-annotated variant site (in lig4s and leukemia; impairs activity); a β-strand; a binding site

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 residue
LIG4 p.Arg278Leu Pathogenic ★★ same residue
LIG4 p.Arg278Cys Likely pathogenic ★ same residue
LIG4 p.Arg278Pro Likely pathogenic ★ same residue
LIG4 p.Arg278Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
LIG4 p.Arg278Gly Pathogenic same residue
LIG4 p.Arg293Ter Pathogenic/Likely pathogenic ★★ same condition
LIG4 p.Arg580Ter Pathogenic/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-arg278 (accessed [today's date]).

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