Is HLCS p.Pro686Leu (c.2057C>T) pathogenic?

HLCS p.Pro686Leu (c.2057C>T) is classified Uncertain significance in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). AlphaMissense: likely pathogenic (0.6267); Very rare (popmax 0.00525%, nfe); Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Pro686Leu (c.2057C>T)?

HLCS p.Pro686Leu (c.2057C>T) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Pro686Leu (c.2057C>T) in the general population?

HLCS p.Pro686Leu (c.2057C>T) is very rare (popmax 0.00525%, nfe) (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.Pro686Leu (c.2057C>T)?

AlphaMissense predicts likely pathogenic (score 0.6267) — an in-silico prediction, not a clinical call.

HLCS p.Pro686Leu

c.2057C>T · rs369068690 · VCV2058378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
AlphaMissense	0.6267	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P539L vs ClinVar P686L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00525% European (non-Finnish) · 62/1,180,036 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0044% 71/1,614,054 alleles · very rare exomes 70/1,461,878 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00525%	19,033
Admixed American	0.005%	19,999
South Asian	0.00439%	22,772
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.Pro686Leu
Coding: c.2057C>T
MANE Select: NM_001352514
dbSNP: rs369068690
Type: single nucleotide variant
Location: chr21:36765076 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 539 UniProt numbering: 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.Pro686Arg Uncertain significance ★ ⚠ same residue
HLCS p.Pro686= 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-pro686leu (accessed [today's date]).

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