Is LIG4 p.Val414= (c.1242A>C) pathogenic?

LIG4 p.Val414= (c.1242A>C) is classified Conflicting classifications of pathogenicity in LIG4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-17). Very rare (popmax 0.00449%, nfe); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Val414= (c.1242A>C)?

LIG4 p.Val414= (c.1242A>C) is associated with DNA ligase IV deficiency, plasma cell myeloma (ClinVar).

How common is LIG4 p.Val414= (c.1242A>C) in the general population?

LIG4 p.Val414= (c.1242A>C) is very rare (popmax 0.00449%, nfe) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Val414=

c.1242A>C · rs150828164 · VCV827984

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Conditions

DNA ligase IV deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.4	GERP -5.3
Overall
CADD	0.173	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00449% European (non-Finnish) · 53/1,179,988 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00341% 55/1,612,144 alleles · very rare exomes 54/1,459,928 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,264
Admixed American	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Val414=
Coding: c.1242A>C
MANE Select: NM_206937
dbSNP: rs150828164
Type: single nucleotide variant
Location: chr13:108210027 (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 414: 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

Also linked: plasma cell myeloma

For LIG4 syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LIG4 p.Val414_Ile415insTer Pathogenic ★ 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
LIG4 p.Gln773Ter 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-val414 (accessed [today's date]).

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