Is HMGCS2 p.Pro201Arg (c.602C>G) pathogenic?

HMGCS2 p.Pro201Arg (c.602C>G) is classified Uncertain significance in HMGCS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1343); Absent from gnomAD v4.1; Associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

What condition is associated with HMGCS2 p.Pro201Arg (c.602C>G)?

HMGCS2 p.Pro201Arg (c.602C>G) is associated with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (ClinVar).

How common is HMGCS2 p.Pro201Arg (c.602C>G) in the general population?

HMGCS2 p.Pro201Arg (c.602C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HMGCS2 p.Pro201Arg (c.602C>G)?

AlphaMissense predicts likely benign (score 0.1343) — an in-silico prediction, not a clinical call.

HMGCS2 p.Pro201Arg

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.602C>G · VCV4771517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1343 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Computational evidence

Protein change
AlphaMissense	0.1343	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 18 kb · p 0.71 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Pro201Arg
Coding: c.602C>G
MANE Select: NM_005518
Type: single nucleotide variant
Location: chr1:119759947 (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.Pro201= Likely benign 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-pro201arg (accessed [today's date]).

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