Is HLCS p.Ser832Phe (c.2495C>T) pathogenic?

HLCS p.Ser832Phe (c.2495C>T) is classified Uncertain significance in HLCS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-24). AlphaMissense: likely benign (0.1223); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with HLCS p.Ser832Phe (c.2495C>T)?

HLCS p.Ser832Phe (c.2495C>T) is associated with Inborn genetic diseases, holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Ser832Phe (c.2495C>T) in the general population?

HLCS p.Ser832Phe (c.2495C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about HLCS p.Ser832Phe (c.2495C>T)?

AlphaMissense predicts likely benign (score 0.1223) — an in-silico prediction, not a clinical call.

HLCS p.Ser832Phe

c.2495C>T · rs1178458399 · VCV2101005

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1223 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1223	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1.4, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	16.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 S685F vs ClinVar S832F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,926 alleles

Overall 0.000124% 2/1,613,792 alleles · very rare exomes 1/1,461,594 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,926
European (non-Finnish)	8.47e-05%	1,179,997

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.Ser832Phe
Coding: c.2495C>T
MANE Select: NM_001352514
dbSNP: rs1178458399
Type: single nucleotide variant
Location: chr21:36754373 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: holocarboxylase synthetase deficiency

Similar variants

HLCS p.Ser832= Likely benign ★ same residue
HLCS p.Ser832Pro Uncertain significance ★ 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-ser832phe (accessed [today's date]).

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