Is LIAS p.Phe17Ser (c.50T>C) pathogenic?

LIAS p.Phe17Ser (c.50T>C) is classified Uncertain significance in LIAS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-17). AlphaMissense: likely benign (0.0794); Very rare (popmax 0.000515%, nfe); Associated with lipoic acid synthetase deficiency.

What condition is associated with LIAS p.Phe17Ser (c.50T>C)?

LIAS p.Phe17Ser (c.50T>C) is associated with lipoic acid synthetase deficiency (ClinVar).

How common is LIAS p.Phe17Ser (c.50T>C) in the general population?

LIAS p.Phe17Ser (c.50T>C) is very rare (popmax 0.000515%, nfe) (gnomAD).

How is Lipoic acid synthetase deficiency inherited?

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

What do computational predictors say about LIAS p.Phe17Ser (c.50T>C)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

LIAS p.Phe17Ser

c.50T>C · rs751814381 · VCV1021868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000515%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lipoic acid synthetase deficiency

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,460 bp · p 0.35 · regional, not allelic
Overall
CADD	16.79	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 0.000515% European (non-Finnish) · 6/1,164,452 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000445% 7/1,573,368 alleles · very rare exomes 7/1,421,092 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,660
European (non-Finnish)grpmax	0.000515%	194,075

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe17Ser
Coding: c.50T>C
MANE Select: NM_006859
dbSNP: rs751814381
Type: single nucleotide variant
Location: chr4:39460794 (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

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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-phe17ser (accessed [today's date]).

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