Is HMGCL p.Pro30= (c.90A>G) pathogenic?

HMGCL p.Pro30= (c.90A>G) is classified Likely benign in HMGCL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-12). Very rare (popmax 0.000678%, nfe); Associated with 3-hydroxy-3-methylglutaric aciduria.

What condition is associated with HMGCL p.Pro30= (c.90A>G)?

HMGCL p.Pro30= (c.90A>G) is associated with 3-hydroxy-3-methylglutaric aciduria (ClinVar).

How common is HMGCL p.Pro30= (c.90A>G) in the general population?

HMGCL p.Pro30= (c.90A>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

How is 3-hydroxy-3-methylglutaric aciduria inherited?

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

HMGCL p.Pro30=

c.90A>G · rs767787302 · VCV1161405

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

3-hydroxy-3-methylglutaric aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.027	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -5.5, phastCons 0.32
Overall
CADD	2.998	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,982 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,030 alleles · very rare exomes 7/1,461,814 · genomes 1/152,216 · joint denominator

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: HMGCL
Protein: p.Pro30=
Coding: c.90A>G
MANE Select: NM_000191
dbSNP: rs767787302
Type: single nucleotide variant
Location: chr1:23820564 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.11 · 4 PDB

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

Disease context

3-hydroxy-3-methylglutaric aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 3-hydroxy-3-methylglutaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

HMGCL p.Pro30Leu Uncertain significance ★★ ⚠ same residue
HMGCL c.144+1G>A Likely pathogenic ★★ same condition
HMGCL c.348+1G>C Likely pathogenic ★★ same condition
HMGCL c.497+1G>A Likely pathogenic ★★ same condition
HMGCL c.497+4A>G Likely pathogenic ★★ same condition
HMGCL c.562-1G>A Pathogenic/Likely pathogenic ★★ same condition
HMGCL c.562-2A>G Likely pathogenic ★★ same condition
HMGCL c.876+1G>C 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/hmgcl-p-pro30 (accessed [today's date]).

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