Is LIAS p.Pro43= (c.129A>G) pathogenic?

LIAS p.Pro43= (c.129A>G) is classified Benign/Likely benign in LIAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0294%, afr); Associated with lipoic acid synthetase deficiency.

What condition is associated with LIAS p.Pro43= (c.129A>G)?

LIAS p.Pro43= (c.129A>G) is associated with lipoic acid synthetase deficiency (ClinVar).

How common is LIAS p.Pro43= (c.129A>G) in the general population?

LIAS p.Pro43= (c.129A>G) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

How is Lipoic acid synthetase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LIAS p.Pro43=

c.129A>G · rs377315137 · VCV540092

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Conditions

lipoic acid synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.67, phastCons 1
Overall
CADD	12.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0294% African / African-American · 22/74,918 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00143% 23/1,613,548 alleles · ultra-rare exomes 10/1,461,308 · genomes 13/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,405
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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: LIAS
Protein: p.Pro43=
Coding: c.129A>G
MANE Select: NM_006859
dbSNP: rs377315137
Type: single nucleotide variant
Location: chr4:39460873 (GRCh38)
Gene constraint: LOEUF 0.988 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.30 · 5 PDB

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

Disease context

lipoic acid synthetase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lipoic acid synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

LIAS c.218+1G>A Likely pathogenic ★★ same condition
LIAS c.954+1G>A Likely pathogenic ★★ same condition
LIAS p.Arg217Ter Pathogenic/Likely pathogenic ★★ same condition
LIAS p.Lys34Ter Pathogenic/Likely pathogenic ★★ same condition
LIAS p.Ala126Thr Uncertain significance ★★ ⚠ same condition
LIAS p.Ala149Gly Uncertain significance ★★ ⚠ same condition
LIAS p.Ala291Val Uncertain significance ★★ ⚠ same condition
LIAS p.Ala8Val 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/lias-p-pro43 (accessed [today's date]).

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