Is LIG4 p.Ser672Arg (c.2016C>G) pathogenic?

LIG4 p.Ser672Arg (c.2016C>G) is classified Uncertain significance in LIG4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-11-01). AlphaMissense: likely benign (0.1474); Ultra-rare (popmax 0.0883%, amr); Associated with severe combined immunodeficiency due to DCLRE1C deficiency.

How common is LIG4 p.Ser672Arg (c.2016C>G) in the general population?

LIG4 p.Ser672Arg (c.2016C>G) is ultra-rare (popmax 0.0883%, amr) (gnomAD).

What do computational predictors say about LIG4 p.Ser672Arg (c.2016C>G)?

AlphaMissense predicts likely benign (score 0.1474) — an in-silico prediction, not a clinical call.

LIG4 p.Ser672Arg

Q: What condition is associated with LIG4 p.Ser672Arg (c.2016C>G)?

LIG4 p.Ser672Arg (c.2016C>G) is associated with severe combined immunodeficiency due to DCLRE1C deficiency, DNA ligase IV deficiency (ClinVar).

Q: How is Severe combined immunodeficiency due to DCLRE1C deficiency inherited?

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

c.2016C>G · rs142144659 · VCV211374

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1474 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0883%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency due to DCLRE1C deficiency

Computational evidence

Protein change
AlphaMissense	0.1474	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -0.8, phastCons 0.07
Regional constraint	o/e 1.01	unconstrained · MANE · 1,269 bp · p 0.81 · regional, not allelic
Overall
CADD	13.24	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0883% Admixed American · 53/60,024 alleles

Filtering AF 0.0693% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0625%

Overall 0.0164% 264/1,614,064 alleles · ultra-rare exomes 211/1,461,800 · genomes 53/152,264 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0883%	1,133
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.015%	6,667
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,402
African / African-American	0.012%	8,336

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.Ser672Arg
Coding: c.2016C>G
MANE Select: NM_206937
dbSNP: rs142144659
Type: single nucleotide variant
Location: chr13:108209253 (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 672: the brct 1 domain; a β-strand; a UniProt-annotated variant site (in lig4s)

Full LIG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency due to DCLRE1C deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: DNA ligase IV deficiency

For Severe combined immunodeficiency due to DCLRE1C deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
LIG4 p.His282Arg 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-ser672arg (accessed [today's date]).

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