Is HMGCS2 p.Ala65= (c.195C>T) pathogenic?

HMGCS2 p.Ala65= (c.195C>T) is classified Likely benign in HMGCS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-03). Absent from gnomAD v4.1; Associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

What condition is associated with HMGCS2 p.Ala65= (c.195C>T)?

HMGCS2 p.Ala65= (c.195C>T) is associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (ClinVar).

How common is HMGCS2 p.Ala65= (c.195C>T) in the general population?

HMGCS2 p.Ala65= (c.195C>T) is absent from gnomAD v4.1 (gnomAD).

HMGCS2 p.Ala65=

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.195C>T · rs1571042762 · VCV1645199

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 2.3	GERP -1.6, phastCons 1
Overall
CADD	9.288	PHRED · no single calibrated threshold — expert panels disagree

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: HMGCS2
Protein: p.Ala65=
Coding: c.195C>T
MANE Select: NM_005518
dbSNP: rs1571042762
Type: single nucleotide variant
Location: chr1:119764536 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.00 · 1 PDB
Residue 65: a β-strand

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 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
HMGCS2 p.Arg501Pro 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-ala65 (accessed [today's date]).

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