Is CLPP p.Leu158Ile (c.472C>A) pathogenic?

CLPP p.Leu158Ile (c.472C>A) is classified Uncertain significance in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: ambiguous (0.5546); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLPP p.Leu158Ile (c.472C>A)?

CLPP p.Leu158Ile (c.472C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CLPP p.Leu158Ile (c.472C>A) in the general population?

CLPP p.Leu158Ile (c.472C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CLPP p.Leu158Ile (c.472C>A)?

AlphaMissense predicts ambiguous (score 0.5546) — an in-silico prediction, not a clinical call.

CLPP p.Leu158Ile

c.472C>A · rs1252361067 · VCV2318597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5546	ambiguous
REVEL	0.349	indeterminate
SaProt	LLR -9.71	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 6,803 bp · p 5e-05 · regional, not allelic
Overall
CADD	26.6	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 0.000339% European (non-Finnish) · 4/1,179,898 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,042 alleles · very rare

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: CLPP
Protein: p.Leu158Ile
Coding: c.472C>A
MANE Select: NM_006012
dbSNP: rs1252361067
Type: single nucleotide variant
Location: chr19:6364556 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 32 PDB
Residue 158: an α-helix

Full CLPP 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

Similar variants

CLPP p.Ala10Ser Uncertain significance ★★ ⚠ same condition
CLPP p.Ala128Thr Uncertain significance ★★ ⚠ same condition
CLPP p.Ala43Thr Uncertain significance ★★ ⚠ same condition
CLPP p.Ala50Thr Uncertain significance ★★ ⚠ same condition
CLPP p.Arg185Trp Uncertain significance ★★ ⚠ same condition
CLPP p.Gly8Ala Uncertain significance ★★ ⚠ same condition
CLPP p.Ile208Val Uncertain significance ★★ ⚠ same condition
CLPP p.Leu58Phe Uncertain significance ★★ ⚠ 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/clpp-p-leu158ile (accessed [today's date]).

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