Is LIG4 p.Asp661= (c.1983T>C) pathogenic?

LIG4 p.Asp661= (c.1983T>C) is classified Conflicting classifications of pathogenicity in LIG4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-01). Rare (popmax 0.102%, amr); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Asp661= (c.1983T>C)?

LIG4 p.Asp661= (c.1983T>C) is associated with DNA ligase IV deficiency, severe combined immunodeficiency due to DCLRE1C deficiency (ClinVar).

How common is LIG4 p.Asp661= (c.1983T>C) in the general population?

LIG4 p.Asp661= (c.1983T>C) is rare (popmax 0.102%, amr) (gnomAD).

How is LIG4 syndrome inherited?

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

LIG4 p.Asp661=

c.1983T>C · rs199638675 · VCV310980

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.102%, amr)

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 -0.83	GERP -2.7
Overall
CADD	0.483	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.102% Admixed American · 61/60,028 alleles

Filtering AF 0.0811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0738%

Overall 0.0289% 466/1,614,108 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.102%	984
Middle Eastern	0.099%	1,010
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,114
European (non-Finnish)	0.0292%	3,430
East Asian	0.029%	3,453
Remaining individualsnot grpmax-eligible	0.0288%	3,472
African / African-American	0.00666%	15,007
South Asian	0.00549%	18,215

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.Asp661=
Coding: c.1983T>C
MANE Select: NM_206937
dbSNP: rs199638675
Type: single nucleotide variant
Location: chr13:108209286 (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 661: the brct 1 domain; a turn; a UniProt-annotated variant site (in lig4s)

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: severe combined immunodeficiency due to DCLRE1C deficiency

For LIG4 syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LIG4 p.Asp661Ala 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
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-asp661 (accessed [today's date]).

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