Is CLPP p.Leu58Arg (c.173T>G) pathogenic?

CLPP p.Leu58Arg (c.173T>G) is classified Conflicting classifications of pathogenicity in CLPP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-05-07). AlphaMissense: likely pathogenic (0.6369); Ultra-rare (popmax 0.0169%, mid); Associated with Perrault syndrome 3.

What condition is associated with CLPP p.Leu58Arg (c.173T>G)?

CLPP p.Leu58Arg (c.173T>G) is associated with Perrault syndrome 3 (ClinVar).

How common is CLPP p.Leu58Arg (c.173T>G) in the general population?

CLPP p.Leu58Arg (c.173T>G) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

How is Perrault syndrome inherited?

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

What do computational predictors say about CLPP p.Leu58Arg (c.173T>G)?

AlphaMissense predicts likely pathogenic (score 0.6369) — an in-silico prediction, not a clinical call.

CLPP p.Leu58Arg

c.173T>G · rs980193170 · VCV500291

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Perrault syndrome 3

Computational evidence

Protein change
AlphaMissense	0.6369	likely pathogenic
REVEL	0.35	indeterminate
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 328 bp · p 0.022 · regional, not allelic
Overall
CADD	29.3	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 0.0169% Middle Eastern · 1/5,910 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000502%

Overall 0.000982% 15/1,527,484 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,910
African / African-American	0.0041%	24,400
European (non-Finnish)	0.000963%	103,885

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.Leu58Arg
Coding: c.173T>G
MANE Select: NM_006012
dbSNP: rs980193170
Type: single nucleotide variant
Location: chr19:6361747 (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 58: an α-helix

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

Disease context

Perrault syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Perrault syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

CLPP p.Leu58Phe Uncertain significance ★★ ⚠ same residue
CLPP c.368-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLPP p.Arg174Cys Uncertain significance ★★ ⚠ same condition
CLPP p.Val264Ala Uncertain significance ★★ ⚠ same condition
CLPP c.555+16G>A Benign/Likely benign ★★ same condition
CLPP c.-5G>A Benign ★★ same condition
CLPP c.661+2T>G Likely pathogenic ★ same condition
CLPP p.Arg78Pro Likely 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/clpp-p-leu58arg (accessed [today's date]).

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