Is HMGCR p.Arg595Cys (c.1783C>T) pathogenic?

HMGCR p.Arg595Cys (c.1783C>T) is classified Uncertain significance in HMGCR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1363); Ultra-rare (popmax 0.015%, amr).

How common is HMGCR p.Arg595Cys (c.1783C>T) in the general population?

HMGCR p.Arg595Cys (c.1783C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about HMGCR p.Arg595Cys (c.1783C>T)?

AlphaMissense predicts likely benign (score 0.1363) — an in-silico prediction, not a clinical call.

HMGCR p.Arg595Cys

c.1783C>T · VCV4527155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1363 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1363	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -11.86	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 5,702 bp · p 8.1e-24 · regional, not allelic
Overall
CADD	33.0	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 0.015% Admixed American · 9/60,014 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000805% 13/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,331

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: HMGCR
Protein: p.Arg595Cys
Coding: c.1783C>T
MANE Select: NM_000859
Type: single nucleotide variant
Location: chr5:75355425 (GRCh38)
Gene constraint: LOEUF 0.447 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.77 · 24 PDB
Residue 595: a β-strand

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

Similar variants

HMGCR p.Arg641Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
HMGCR p.Arg443Gln Likely pathogenic ★ ⚠ same type
HMGCR p.Arg840Ter Likely pathogenic ★ same type
HMGCR p.Asp623Asn Likely pathogenic ★ ⚠ same type
HMGCR p.Gly822Asp Pathogenic ★ ⚠ same type
HMGCR p.Ala667Thr Uncertain significance ★ ⚠ same type
HMGCR p.Ala759Thr Uncertain significance ★ ⚠ same type
HMGCR p.Ala888Val Uncertain significance ★ ⚠ same type

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/hmgcr-p-arg595cys (accessed [today's date]).

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