Is HMGCS2 p.Ser371Cys (c.1112C>G) pathogenic?

HMGCS2 p.Ser371Cys (c.1112C>G) is classified Uncertain significance in HMGCS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.1464); Ultra-rare (popmax 0.0333%, amr); Associated with Inborn genetic diseases.

What condition is associated with HMGCS2 p.Ser371Cys (c.1112C>G)?

HMGCS2 p.Ser371Cys (c.1112C>G) is associated with Inborn genetic diseases, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (ClinVar).

How common is HMGCS2 p.Ser371Cys (c.1112C>G) in the general population?

HMGCS2 p.Ser371Cys (c.1112C>G) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about HMGCS2 p.Ser371Cys (c.1112C>G)?

AlphaMissense predicts likely benign (score 0.1464) — an in-silico prediction, not a clinical call.

HMGCS2 p.Ser371Cys

c.1112C>G · rs762536796 · VCV2138012

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1464 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1464	likely benign
REVEL	0.664	pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.81, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 18 kb · p 0.71 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,004 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0013% 21/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Ser371Cys
Coding: c.1112C>G
MANE Select: NM_005518
dbSNP: rs762536796
Type: single nucleotide variant
Location: chr1:119755502 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.00 · 1 PDB
Residue 371: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

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-ser371cys (accessed [today's date]).

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