Is LIG4 p.Ala211Pro (c.631G>C) pathogenic?

LIG4 p.Ala211Pro (c.631G>C) is classified Uncertain significance in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9848); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LIG4 p.Ala211Pro (c.631G>C)?

LIG4 p.Ala211Pro (c.631G>C) is associated with Inborn genetic diseases (ClinVar).

How common is LIG4 p.Ala211Pro (c.631G>C) in the general population?

LIG4 p.Ala211Pro (c.631G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about LIG4 p.Ala211Pro (c.631G>C)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

LIG4 p.Ala211Pro

c.631G>C · rs2501619459 · VCV2330692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic · top 2% in LIG4
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -15.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,395 bp · p 0.027 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000169% European (non-Finnish) · 2/1,179,962 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,682 alleles · very rare exomes 2/1,461,388 · genomes 0/152,294 · joint denominator

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.Ala211Pro
Coding: c.631G>C
MANE Select: NM_206937
dbSNP: rs2501619459
Type: single nucleotide variant
Location: chr13:108210638 (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 211: an α-helix

Full LIG4 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

LIG4 p.Gly303Arg Likely pathogenic ★★ same condition
LIG4 p.Pro248Leu Likely pathogenic ★★ same condition
LIG4 p.Ala523Gly Uncertain significance ★★ ⚠ same condition
LIG4 p.Ala702Gly Uncertain significance ★★ ⚠ same condition
LIG4 p.Ala824Ser Uncertain significance ★★ ⚠ same condition
LIG4 p.Arg25Gln Uncertain significance ★★ ⚠ same condition
LIG4 p.Arg756His Uncertain significance ★★ ⚠ same condition
LIG4 p.Arg756Ser 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/lig4-p-ala211pro (accessed [today's date]).

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