Is LIG4 p.Pro231Ser (c.691C>T) pathogenic?

LIG4 p.Pro231Ser (c.691C>T) is classified Conflicting classifications of pathogenicity in LIG4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.1088); Rare (popmax 0.139%, afr); Associated with plasma cell myeloma.

What condition is associated with LIG4 p.Pro231Ser (c.691C>T)?

LIG4 p.Pro231Ser (c.691C>T) is associated with plasma cell myeloma, DNA ligase IV deficiency (ClinVar).

How common is LIG4 p.Pro231Ser (c.691C>T) in the general population?

LIG4 p.Pro231Ser (c.691C>T) is rare (popmax 0.139%, afr) (gnomAD).

How is Multiple myeloma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LIG4 p.Pro231Ser (c.691C>T)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

LIG4 p.Pro231Ser

c.691C>T · rs3093765 · VCV834697

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

plasma cell myeloma

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.549	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,395 bp · p 0.027 · regional, not allelic
Overall
CADD	24.4	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 0.139% African / African-American · 104/74,902 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.0075% 121/1,613,044 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.139%	720
Admixed American	0.0267%	3,749
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Pro231Ser
Coding: c.691C>T
MANE Select: NM_206937
dbSNP: rs3093765
Type: single nucleotide variant
Location: chr13:108210578 (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 231: a UniProt-annotated variant site (in); a β-strand

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

Disease context

plasma cell myeloma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: DNA ligase IV deficiency

For Multiple myeloma (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

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-pro231ser (accessed [today's date]).

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