Is HLCS p.Ser430= (c.1290C>T) pathogenic?

HLCS p.Ser430= (c.1290C>T) is classified Likely benign in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-05). Very rare (popmax 0.00329%, sas); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Ser430= (c.1290C>T)?

HLCS p.Ser430= (c.1290C>T) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Ser430= (c.1290C>T) in the general population?

HLCS p.Ser430= (c.1290C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Ser430=

c.1290C>T · rs1472760580 · VCV763796

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.7	GERP -4.3
Overall
CADD	2.775	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,092 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000743% 12/1,614,078 alleles · very rare exomes 10/1,461,890 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,364
East Asian	0.00223%	44,888
Admixed American	0.00167%	60,006
Finnishnot grpmax-eligible	0.00156%	64,036
European (non-Finnish)	0.000508%	196,674

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: HLCS
Protein: p.Ser430=
Coding: c.1290C>T
MANE Select: NM_001352514
dbSNP: rs1472760580
Type: single nucleotide variant
Location: chr21:36936596 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33

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

Disease context

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

For Holocarboxylase synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

HLCS p.Ser430fs Likely pathogenic ★★ same residue
HLCS c.1620+2T>G Likely pathogenic ★★ same condition
HLCS c.1621-2A>G Likely pathogenic ★★ same condition
HLCS c.1892+1G>A Likely pathogenic ★★ same condition
HLCS c.1960+5G>A Pathogenic ★★ same condition
HLCS c.2121+1G>A Pathogenic/Likely pathogenic ★★ same condition
HLCS c.2237-2A>G Likely pathogenic ★★ same condition
HLCS c.2450+2T>A Likely pathogenic ★★ 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/hlcs-p-ser430 (accessed [today's date]).

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