Is HLCS p.Arg678= (c.2034A>G) pathogenic?

HLCS p.Arg678= (c.2034A>G) is classified Likely benign in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-09). Very rare (popmax 0.00833%, amr); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Arg678= (c.2034A>G)?

HLCS p.Arg678= (c.2034A>G) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Arg678= (c.2034A>G) in the general population?

HLCS p.Arg678= (c.2034A>G) is very rare (popmax 0.00833%, amr) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Arg678=

c.2034A>G · rs945618984 · VCV1099062

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 0.009	GERP -4.8, phastCons 0.002
Overall
CADD	13.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000434% 7/1,613,894 alleles · very rare exomes 5/1,461,842 · genomes 2/152,052 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
European (non-Finnish)	0.000169%	589,984

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.Arg678=
Coding: c.2034A>G
MANE Select: NM_001352514
dbSNP: rs945618984
Type: single nucleotide variant
Location: chr21:36765099 (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.Arg678Lys 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-arg678 (accessed [today's date]).

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