Is HLCS p.Arg330Pro (c.989G>C) pathogenic?

HLCS p.Arg330Pro (c.989G>C) is classified Uncertain significance in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-22). AlphaMissense: likely pathogenic (0.6742); Absent from gnomAD v4.1; Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Arg330Pro (c.989G>C)?

HLCS p.Arg330Pro (c.989G>C) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Arg330Pro (c.989G>C) in the general population?

HLCS p.Arg330Pro (c.989G>C) is absent from gnomAD v4.1 (gnomAD).

How is Holocarboxylase synthetase deficiency inherited?

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

What do computational predictors say about HLCS p.Arg330Pro (c.989G>C)?

AlphaMissense predicts likely pathogenic (score 0.6742) — an in-silico prediction, not a clinical call.

HLCS p.Arg330Pro

c.989G>C · rs368754318 · VCV860908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6742 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
AlphaMissense	0.6742	likely pathogenic
REVEL	0.616	indeterminate
SaProt	LLR -14.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6	GERP -4.4
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	3.249	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R183P vs ClinVar R330P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HLCS
Protein: p.Arg330Pro
Coding: c.989G>C
MANE Select: NM_001352514
dbSNP: rs368754318
Type: single nucleotide variant
Location: chr21:36936897 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 183 UniProt numbering: a UniProt-annotated variant site (in hlcs deficiency; has normal or low km values for biotin (non-km mutant))

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.Arg330Trp Uncertain significance ★★ ⚠ same residue
HLCS p.Arg330= 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-arg330pro (accessed [today's date]).

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