Is LIG4 p.Ala797Ser (c.2389G>T) pathogenic?

LIG4 p.Ala797Ser (c.2389G>T) is classified Conflicting classifications of pathogenicity in LIG4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.0983); Rare (popmax 0.39%, afr); Associated with DNA ligase IV deficiency.

What condition is associated with LIG4 p.Ala797Ser (c.2389G>T)?

LIG4 p.Ala797Ser (c.2389G>T) is associated with DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Ala797Ser (c.2389G>T) in the general population?

LIG4 p.Ala797Ser (c.2389G>T) is rare (popmax 0.39%, afr) (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.Ala797Ser (c.2389G>T)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

LIG4 p.Ala797Ser

c.2389G>T · rs138936350 · VCV533825

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.39%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DNA ligase IV deficiency

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -4.25	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 1.8	GERP 1.9, phastCons 0.93
Regional constraint	o/e 1.01	unconstrained · MANE · 1,269 bp · p 0.81 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.39% African / African-American · 293/75,040 alleles

Filtering AF 0.354% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.339%

Overall 0.0199% 322/1,614,082 alleles · rare exomes 142/1,461,794 · genomes 180/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.39%	256
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed American	0.0183%	5,457
European (non-Finnish)	8.47e-05%	1,179,979

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.Ala797Ser
Coding: c.2389G>T
MANE Select: NM_206937
dbSNP: rs138936350
Type: single nucleotide variant
Location: chr13:108208880 (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 797: an α-helix; 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

For LIG4 syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LIG4 p.Ala797Val 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-ala797ser (accessed [today's date]).

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