Is HLCS p.Ser754fs (c.2260dup) pathogenic?

HLCS p.Ser754fs (c.2260dup) is classified Pathogenic/Likely pathogenic in HLCS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-11). Very rare (popmax 0.00801%, afr); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Ser754fs (c.2260dup)?

HLCS p.Ser754fs (c.2260dup) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Ser754fs (c.2260dup) in the general population?

HLCS p.Ser754fs (c.2260dup) is very rare (popmax 0.00801%, afr) (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

HLCS p.Ser754fs

c.2260dup · rs766163167 · VCV553733

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Overall
CADD	35.0	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 0.00801% African / African-American · 6/74,908 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,614,054 alleles · very rare exomes 0/1,461,874 · genomes 6/152,180 · joint denominator

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.Ser754fs
Coding: c.2260dup
MANE Select: NM_001352514
dbSNP: rs766163167
Type: Duplication
Location: chr21:36756731 (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.Ser754= Likely benign ★ same residue
HLCS p.Ala409fs Likely pathogenic ★★ same condition
HLCS p.Ile366fs Pathogenic ★★ same condition
HLCS p.Met590fs Pathogenic/Likely pathogenic ★★ same condition
HLCS p.Thr172fs Pathogenic/Likely pathogenic ★★ same condition
HLCS p.Val659fs Pathogenic/Likely pathogenic ★★ same condition
HLCS c.1681dup Likely pathogenic ★ same condition
HLCS p.Ala646fs 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-ser754fs (accessed [today's date]).

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