Is CLU p.Val398Ile (c.1192G>A) pathogenic?

CLU p.Val398Ile (c.1192G>A) is classified Likely benign in CLU (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-01). AlphaMissense: likely benign (0.0736); Very rare (popmax 0.0022%, sas).

How common is CLU p.Val398Ile (c.1192G>A) in the general population?

CLU p.Val398Ile (c.1192G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CLU p.Val398Ile (c.1192G>A)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

CLU p.Val398Ile

c.1192G>A · VCV3389077

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.53	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 -3.2	GERP -5.1
Regional constraint	o/e 0.88	unconstrained · MANE · 8,245 bp · p 0.011 · regional, not allelic
Overall
CADD	0.137	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 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000805% 13/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000847%	118,004

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.Val398Ile
Coding: c.1192G>A
MANE Select: NM_001831
Type: single nucleotide variant
Location: chr8:27598608 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.11 · 2 PDB
Residue 398: a β-strand

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

Similar variants

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
CLU p.Asp397= Benign/Likely benign ★★ same type
CLU p.His252= Likely benign ★★ same type
CLU p.Pro318= Benign ★★ same type
CLU p.Ser396Leu 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-val398ile (accessed [today's date]).

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