Is HMGCS2 p.Arg288= (c.862C>A) pathogenic?

HMGCS2 p.Arg288= (c.862C>A) is classified Benign/Likely benign in HMGCS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-18). Rare (popmax 0.908%, afr); Associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

What condition is associated with HMGCS2 p.Arg288= (c.862C>A)?

HMGCS2 p.Arg288= (c.862C>A) is associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (ClinVar).

How common is HMGCS2 p.Arg288= (c.862C>A) in the general population?

HMGCS2 p.Arg288= (c.862C>A) is rare (popmax 0.908%, afr) (gnomAD).

HMGCS2 p.Arg288=

Q: How is 3-hydroxy-3-methylglutaryl-CoA synthase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.862C>A · rs142637231 · VCV292333

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.908%, afr)

Conditions

3-hydroxy-3-methylglutaryl-CoA synthase 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 3.6	GERP 0.84, phastCons 0.66
Overall
CADD	4.836	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.908% African / African-American · 681/74,992 alleles

Filtering AF 0.852% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.829%

Overall 0.0469% 757/1,613,770 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.908%	110
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.03%	3,334
South Asian	0.0132%	7,590
European (non-Finnish)	8.48e-05%	1,179,686

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: HMGCS2
Protein: p.Arg288=
Coding: c.862C>A
MANE Select: NM_005518
dbSNP: rs142637231
Type: single nucleotide variant
Location: chr1:119757427 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.00 · 1 PDB
Residue 288: an α-helix

Full HMGCS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-hydroxy-3-methylglutaryl-CoA synthase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

HMGCS2 p.Arg288Ter Pathogenic ★★ same residue
HMGCS2 p.Arg288Gln Uncertain significance ★ ⚠ same residue
HMGCS2 p.Arg288Gly Uncertain significance ★ ⚠ same residue
HMGCS2 c.1016+1G>A Pathogenic ★★ same condition
HMGCS2 c.1187+1G>C Likely pathogenic ★★ same condition
HMGCS2 c.685+2T>A Likely pathogenic ★★ same condition
HMGCS2 p.Arg424Ter Pathogenic/Likely pathogenic ★★ same condition
HMGCS2 p.Arg500His 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/hmgcs2-p-arg288 (accessed [today's date]).

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