Is HLCS p.Ala646= (c.1938G>C) pathogenic?

HLCS p.Ala646= (c.1938G>C) is classified Likely benign in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). Absent from gnomAD v4.1; Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Ala646= (c.1938G>C)?

HLCS p.Ala646= (c.1938G>C) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Ala646= (c.1938G>C) in the general population?

HLCS p.Ala646= (c.1938G>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.

HLCS p.Ala646=

c.1938G>C · rs370347318 · VCV1115862

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -5.3
Overall
CADD	0.124	PHRED · no single calibrated threshold — expert panels disagree

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.Ala646=
Coding: c.1938G>C
MANE Select: NM_001352514
dbSNP: rs370347318
Type: single nucleotide variant
Location: chr21:36767240 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 646: the bpl/lpl catalytic domain

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.Ala646Thr Uncertain significance ★ ⚠ same residue
HLCS p.Ala646Val Uncertain significance ★ ⚠ same residue
HLCS p.Ala646fs Likely pathogenic ★ 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

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-ala646 (accessed [today's date]).

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