Is HLCS p.Val365Phe (c.1093G>T) pathogenic?

HLCS p.Val365Phe (c.1093G>T) is classified Conflicting classifications of pathogenicity in HLCS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-06-03). AlphaMissense: ambiguous (0.5147); Absent from gnomAD v4.1; Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Val365Phe (c.1093G>T)?

HLCS p.Val365Phe (c.1093G>T) is associated with holocarboxylase synthetase deficiency (ClinVar).

How common is HLCS p.Val365Phe (c.1093G>T) in the general population?

HLCS p.Val365Phe (c.1093G>T) 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.Val365Phe (c.1093G>T)?

AlphaMissense predicts ambiguous (score 0.5147) — an in-silico prediction, not a clinical call.

HLCS p.Val365Phe

c.1093G>T · rs1569216588 · VCV570638

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5147 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
AlphaMissense	0.5147	ambiguous
REVEL	0.728	pathogenic-leaning
SaProt	LLR -12.39	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	24.1	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 V218F vs ClinVar V365F) — 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.Val365Phe
Coding: c.1093G>T
MANE Select: NM_001352514
dbSNP: rs1569216588
Type: single nucleotide variant
Location: chr21:36936793 (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 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
HLCS c.2450+2T>A Likely pathogenic ★★ same condition
HLCS c.2451-1G>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-val365phe (accessed [today's date]).

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