Is HLCS p.Arg604= (c.1812C>T) pathogenic?

HLCS p.Arg604= (c.1812C>T) is classified Likely benign in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-01). Very rare (popmax 8.47e-05%, nfe); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Arg604= (c.1812C>T)?

HLCS p.Arg604= (c.1812C>T) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Arg604= (c.1812C>T) in the general population?

HLCS p.Arg604= (c.1812C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Arg604=

c.1812C>T · rs2517422794 · VCV2105321

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

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 -1.7	GERP -3.4
Overall
CADD	2.105	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,888 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: HLCS
Protein: p.Arg604=
Coding: c.1812C>T
MANE Select: NM_001352514
dbSNP: rs2517422794
Type: single nucleotide variant
Location: chr21:36896940 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 604: the bpl/lpl catalytic domain

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.Arg604Cys Uncertain significance ★ ⚠ same residue
HLCS p.Arg604His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg604 (accessed [today's date]).

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