Is LIG4 p.Pro809Ala (c.2425C>G) pathogenic?

LIG4 p.Pro809Ala (c.2425C>G) is classified Uncertain significance in LIG4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-08-11). AlphaMissense: likely benign (0.0862); Ultra-rare (popmax 0.0329%, mid); Associated with severe combined immunodeficiency due to DCLRE1C deficiency.

How common is LIG4 p.Pro809Ala (c.2425C>G) in the general population?

LIG4 p.Pro809Ala (c.2425C>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about LIG4 p.Pro809Ala (c.2425C>G)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

LIG4 p.Pro809Ala

Q: What condition is associated with LIG4 p.Pro809Ala (c.2425C>G)?

LIG4 p.Pro809Ala (c.2425C>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.2425C>G · rs137899041 · VCV647972

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency due to DCLRE1C deficiency

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -7.41	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 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,269 bp · p 0.81 · regional, not allelic
Overall
CADD	21.5	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00551% 89/1,613,956 alleles · ultra-rare exomes 79/1,461,812 · genomes 10/152,144 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0912%	1,096
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0112%	8,926
European (non-Finnish)	0.00381%	26,223
African / African-American	0.00134%	74,892

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro809Ala
Coding: c.2425C>G
MANE Select: NM_206937
dbSNP: rs137899041
Type: single nucleotide variant
Location: chr13:108208844 (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 809: an α-helix; the brct 2 domain; 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.Pro809Leu Uncertain significance ★★ ⚠ same residue
LIG4 p.Pro809= Likely benign ★ same residue
LIG4 p.Pro809fs 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

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-pro809ala (accessed [today's date]).

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