Is HLCS p.Val243Ile (c.727G>A) pathogenic?

HLCS p.Val243Ile (c.727G>A) is classified Benign in HLCS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0787); Common (popmax 11.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with holocarboxylase synthetase deficiency.

What condition is associated with HLCS p.Val243Ile (c.727G>A)?

HLCS p.Val243Ile (c.727G>A) is associated with holocarboxylase synthetase deficiency (ClinVar).

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.Val243Ile (c.727G>A)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

HLCS p.Val243Ile

Q: How common is HLCS p.Val243Ile (c.727G>A) in the general population?

HLCS p.Val243Ile (c.727G>A) is common (popmax 11.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.727G>A · rs61732502 · VCV137550

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

holocarboxylase synthetase deficiency

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.9	GERP -4
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	0.003	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 V96I vs ClinVar V243I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.1% African / African-American · 8,342/74,992 alleles

Filtering AF 10.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.8%

Overall 1.43% 23,111/1,614,104 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.1%	9
South Asian	4.69%	21
East Asian	3.77%	27
Finnishnot grpmax-eligible	1.76%	57
Remaining individualsnot grpmax-eligible	1.65%	61
Admixed American	1.25%	80
Middle Eastern	1.04%	96
European (non-Finnish)	0.489%	204
Ashkenazi Jewishnot grpmax-eligible	0.203%	493

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.Val243Ile
Coding: c.727G>A
MANE Select: NM_001352514
dbSNP: rs61732502
Type: single nucleotide variant
Location: chr21:36937159 (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 p.Val243fs 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
HLCS c.2237-2A>G Likely pathogenic ★★ same condition
HLCS c.2450+2T>A 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-val243ile (accessed [today's date]).

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