Is LIG3 p.Pro366Ala (c.1096C>G) pathogenic?

LIG3 p.Pro366Ala (c.1096C>G) is classified Uncertain significance in LIG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.0719); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with LIG3 p.Pro366Ala (c.1096C>G)?

LIG3 p.Pro366Ala (c.1096C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LIG3 p.Pro366Ala (c.1096C>G) in the general population?

LIG3 p.Pro366Ala (c.1096C>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about LIG3 p.Pro366Ala (c.1096C>G)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

LIG3 p.Pro366Ala

c.1096C>G · VCV3867117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 4.7e-07 · regional, not allelic
Overall
CADD	23.4	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 0.016% African / African-American · 12/74,892 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000805% 13/1,613,908 alleles · ultra-rare exomes 5/1,461,798 · genomes 8/152,110 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,241
European (non-Finnish)	8.47e-05%	1,179,967

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.Pro366Ala
Coding: c.1096C>G
MANE Select: NM_013975
Type: single nucleotide variant
Location: chr17:34991725 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 13 PDB
Residue 366: a UniProt-annotated variant site (in mtdps20); an α-helix

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.Pro366Arg Uncertain significance ★ ⚠ same residue
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

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-pro366ala (accessed [today's date]).

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