Is LIG4 p.Asp368Val (c.1103A>T) pathogenic?

LIG4 p.Asp368Val (c.1103A>T) is classified Conflicting classifications of pathogenicity in LIG4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-13). AlphaMissense: likely pathogenic (0.9905); Absent from gnomAD v4.1; Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Asp368Val (c.1103A>T)?

LIG4 p.Asp368Val (c.1103A>T) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Asp368Val (c.1103A>T) in the general population?

LIG4 p.Asp368Val (c.1103A>T) is absent from gnomAD v4.1 (gnomAD).

How is LIG4 syndrome inherited?

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

What do computational predictors say about LIG4 p.Asp368Val (c.1103A>T)?

AlphaMissense predicts likely pathogenic (score 0.9905) — an in-silico prediction, not a clinical call.

LIG4 p.Asp368Val

c.1103A>T · rs1220876973 · VCV636382

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9905 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DNA ligase IV deficiency

Computational evidence

Protein change
AlphaMissense	0.9905	likely pathogenic · top 1% in LIG4
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -17.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,395 bp · p 0.027 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LIG4
Protein: p.Asp368Val
Coding: c.1103A>T
MANE Select: NM_206937
dbSNP: rs1220876973
Type: single nucleotide variant
Location: chr13:108210166 (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 368: a β-strand

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.Asp368Asn Uncertain significance ★ ⚠ same residue
LIG4 p.Asp368Tyr Uncertain significance ★ ⚠ same residue
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

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-asp368val (accessed [today's date]).

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