Is LIG3 p.Ser755Arg (c.2265C>A) pathogenic?

LIG3 p.Ser755Arg (c.2265C>A) is classified Uncertain significance in LIG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-11). AlphaMissense: ambiguous (0.5221); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with LIG3 p.Ser755Arg (c.2265C>A)?

LIG3 p.Ser755Arg (c.2265C>A) is associated with Inborn genetic diseases (ClinVar).

How common is LIG3 p.Ser755Arg (c.2265C>A) in the general population?

LIG3 p.Ser755Arg (c.2265C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about LIG3 p.Ser755Arg (c.2265C>A)?

AlphaMissense predicts ambiguous (score 0.5221) — an in-silico prediction, not a clinical call.

LIG3 p.Ser755Arg

c.2265C>A · rs531599539 · VCV3118717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5221	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -8.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 4.7e-07 · regional, not allelic
Overall
CADD	22.6	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000805% 13/1,613,922 alleles · ultra-rare exomes 11/1,461,744 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00333%	30,003
South Asian	0.00329%	30,362
European (non-Finnish)	0.000593%	168,558

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: LIG3
Protein: p.Ser755Arg
Coding: c.2265C>A
MANE Select: NM_013975
dbSNP: rs531599539
Type: single nucleotide variant
Location: chr17:34999790 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 13 PDB
Residue 755: a UniProt-annotated variant site (in mtdps20)

Full LIG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LIG3 p.Gln398Arg Uncertain significance ★★ ⚠ same condition
LIG3 p.Ser248Asn Uncertain significance ★★ ⚠ same condition
LIG3 p.Arg942Gln Benign/Likely benign ★★ same condition
LIG3 c.548-1G>C Uncertain significance ★ same condition
LIG3 p.Ala188Val Uncertain significance ★ ⚠ same condition
LIG3 p.Ala271Thr Uncertain significance ★ ⚠ same condition
LIG3 p.Ala432Thr Uncertain significance ★ ⚠ same condition
LIG3 p.Ala458Thr Uncertain significance ★ ⚠ 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/lig3-p-ser755arg (accessed [today's date]).

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