Is HLCS p.Arg300= (c.900G>A) pathogenic?

HLCS p.Arg300= (c.900G>A) is classified Benign/Likely benign in HLCS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Rare (popmax 0.786%, afr); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Arg300= (c.900G>A)?

HLCS p.Arg300= (c.900G>A) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Arg300= (c.900G>A) in the general population?

HLCS p.Arg300= (c.900G>A) is rare (popmax 0.786%, afr) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Arg300=

c.900G>A · rs146019354 · VCV702392

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.786%, afr)

Conditions

holocarboxylase 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 0.49	GERP -2.3, phastCons 0.006
Overall
CADD	4.272	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.786% African / African-American · 590/75,020 alleles

Filtering AF 0.734% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.713%

Overall 0.04% 645/1,614,146 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.786%	127
Middle Eastern	0.0825%	1,212
Admixed American	0.0433%	2,308
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)	0.000339%	295,010

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.Arg300=
Coding: c.900G>A
MANE Select: NM_001352514
dbSNP: rs146019354
Type: single nucleotide variant
Location: chr21:36936986 (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.Arg300Lys Uncertain significance ★ ⚠ 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-arg300 (accessed [today's date]).

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