Is HLCS p.Ter874= (c.2622A>G) pathogenic?

HLCS p.Ter874= (c.2622A>G) is classified Likely benign in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-14). Ultra-rare (popmax 0.0165%, mid); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Ter874= (c.2622A>G)?

HLCS p.Ter874= (c.2622A>G) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Ter874= (c.2622A>G) in the general population?

HLCS p.Ter874= (c.2622A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Ter874=

c.2622A>G · rs375809125 · VCV1139420

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	Δ0.64	donor loss · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP -0.7, phastCons 1
Overall
CADD	6.315	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 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00112% 18/1,613,744 alleles · ultra-rare exomes 11/1,461,604 · genomes 7/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,068
African / African-American	0.016%	6,243
Admixed American	0.00333%	29,995
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,060

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.Ter874=
Coding: c.2622A>G
MANE Select: NM_001352514
dbSNP: rs375809125
Type: single nucleotide variant
Location: chr21:36754246 (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 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
HLCS c.2451-1G>A Pathogenic/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-ter874 (accessed [today's date]).

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