Is LIG4 p.Phe778Val (c.2332T>G) pathogenic?

LIG4 p.Phe778Val (c.2332T>G) is classified Uncertain significance in LIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: ambiguous (0.3488); Very rare (popmax 0.00266%, afr); Associated with Inborn genetic diseases.

What condition is associated with LIG4 p.Phe778Val (c.2332T>G)?

LIG4 p.Phe778Val (c.2332T>G) is associated with Inborn genetic diseases (ClinVar).

How common is LIG4 p.Phe778Val (c.2332T>G) in the general population?

LIG4 p.Phe778Val (c.2332T>G) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about LIG4 p.Phe778Val (c.2332T>G)?

AlphaMissense predicts ambiguous (score 0.3488) — an in-silico prediction, not a clinical call.

LIG4 p.Phe778Val

c.2332T>G · VCV4097788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3488	ambiguous
REVEL	0.382	indeterminate
SaProt	LLR -9.95	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,269 bp · p 0.81 · regional, not allelic
Overall
CADD	24.3	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 0.00266% African / African-American · 2/75,060 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,332 alleles · very rare

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.Phe778Val
Coding: c.2332T>G
MANE Select: NM_206937
Type: single nucleotide variant
Location: chr13:108208937 (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 778: an α-helix; a UniProt-annotated variant site (in lig4s)

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.Phe778_Ser779insTer Likely pathogenic ★ same residue
LIG4 p.Phe778= Likely benign ★ same residue
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

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-phe778val (accessed [today's date]).

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