Is HMGCS2 p.Ser248= (c.744G>A) pathogenic?

HMGCS2 p.Ser248= (c.744G>A) is classified Likely benign in HMGCS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-02). Ultra-rare (popmax 0.0165%, mid); Associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

What condition is associated with HMGCS2 p.Ser248= (c.744G>A)?

HMGCS2 p.Ser248= (c.744G>A) is associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (ClinVar).

How common is HMGCS2 p.Ser248= (c.744G>A) in the general population?

HMGCS2 p.Ser248= (c.744G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

HMGCS2 p.Ser248=

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.744G>A · rs1219952938 · VCV1345327

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -11	GERP -3.8
Overall
CADD	0.165	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00105% 17/1,614,068 alleles · ultra-rare exomes 17/1,461,798 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	0.00119%	84,283

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.Ser248=
Coding: c.744G>A
MANE Select: NM_005518
dbSNP: rs1219952938
Type: single nucleotide variant
Location: chr1:119759224 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.00 · 1 PDB

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.Ser248Leu 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.Arg288Ter Pathogenic ★★ same condition
HMGCS2 p.Arg424Ter Pathogenic/Likely pathogenic ★★ same condition
HMGCS2 p.Arg500His Pathogenic/Likely pathogenic ★★ ⚠ same condition
HMGCS2 p.Arg501Gln 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-ser248 (accessed [today's date]).

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