Is CLU p.Arg182His (c.545G>A) pathogenic?

CLU p.Arg182His (c.545G>A) is classified Likely benign in CLU (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-30). AlphaMissense: likely benign (0.0773); Rare (popmax 0.123%, eas); Associated with CLU-related disorder.

What condition is associated with CLU p.Arg182His (c.545G>A)?

CLU p.Arg182His (c.545G>A) is associated with CLU-related disorder (ClinVar).

How common is CLU p.Arg182His (c.545G>A) in the general population?

CLU p.Arg182His (c.545G>A) is rare (popmax 0.123%, eas) (gnomAD).

What do computational predictors say about CLU p.Arg182His (c.545G>A)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

CLU p.Arg182His

c.545G>A · VCV3354350

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLU-related disorder

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.51	GERP 0.9
Regional constraint	o/e 0.88	unconstrained · MANE · 8,245 bp · p 0.011 · regional, not allelic
Overall
CADD	16.43	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 0.123% East Asian · 55/44,884 alleles

Filtering AF 0.0967% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0948%

Overall 0.0879% 1,419/1,614,174 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.17%	587
East Asiangrpmax	0.123%	816
European (non-Finnish)	0.102%	985
Remaining individualsnot grpmax-eligible	0.0512%	1,953
South Asian	0.0165%	6,072
African / African-American	0.008%	12,508
Admixed American	0.00666%	15,006

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLU
Protein: p.Arg182His
Coding: c.545G>A
MANE Select: NM_001831
Type: single nucleotide variant
Location: chr8:27605208 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.11 · 2 PDB
Residue 182: a disulfide bond; an α-helix

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

Disease context

CLU-related disorder

Similar variants

CLU c.*9T>C Likely benign same condition
CLU p.Lys40= Likely benign same condition
CLU p.Val20= Likely benign same condition
CLU p.Val406= Likely benign same condition
CLU p.Ala438= Likely benign ★★ same type
CLU p.Asn64= Likely benign ★★ same type
CLU p.Asp328= Benign ★★ same type
CLU p.Asp328Asn Benign ★★ 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/clu-p-arg182his (accessed [today's date]).

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