Is HLCS p.Arg712Ter (c.2134C>T) pathogenic?

HLCS p.Arg712Ter (c.2134C>T) is classified Pathogenic in HLCS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-07-22). Very rare (popmax 0.00892%, eas); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Arg712Ter (c.2134C>T)?

HLCS p.Arg712Ter (c.2134C>T) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Arg712Ter (c.2134C>T) in the general population?

HLCS p.Arg712Ter (c.2134C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Arg712Ter

c.2134C>T · rs772791252 · VCV426486

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Overall
CADD	53.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,848 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00156% 25/1,607,176 alleles · very rare exomes 21/1,455,024 · genomes 4/152,152 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,212
Remaining individualsnot grpmax-eligible	0.00321%	31,130
African / African-American	0.00268%	37,383
Finnishnot grpmax-eligible	0.00156%	64,008
European (non-Finnish)	0.00128%	78,253
South Asian	0.0011%	90,954

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.Arg712Ter
Coding: c.2134C>T
MANE Select: NM_001352514
dbSNP: rs772791252
Type: single nucleotide variant
Location: chr21:36759829 (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.Arg712Gln Uncertain significance ★★ ⚠ same residue
HLCS p.Arg712= Likely benign ★ 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-arg712ter (accessed [today's date]).

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