Is CLPP p.Ile115Phe (c.343A>T) pathogenic?

CLPP p.Ile115Phe (c.343A>T) is classified Uncertain significance in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.00161%, nfe).

How common is CLPP p.Ile115Phe (c.343A>T) in the general population?

CLPP p.Ile115Phe (c.343A>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CLPP p.Ile115Phe (c.343A>T)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

CLPP p.Ile115Phe

c.343A>T · VCV3388641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic
REVEL	0.599	indeterminate
SaProt	LLR -13.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 6,803 bp · p 5e-05 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,179,778 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,613,742 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.Ile115Phe
Coding: c.343A>T
MANE Select: NM_006012
Type: single nucleotide variant
Location: chr19:6362518 (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 115: a β-strand

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

Similar variants

CLPP c.368-2A>G Pathogenic/Likely pathogenic ★★ same type
CLPP p.Ala10Gly Uncertain significance ★★ ⚠ same type
CLPP p.Ala10Ser Uncertain significance ★★ ⚠ same type
CLPP p.Ala128Thr Uncertain significance ★★ ⚠ same type
CLPP p.Ala223Thr Uncertain significance ★★ ⚠ same type
CLPP p.Ala43Thr Uncertain significance ★★ ⚠ same type
CLPP p.Ala50Thr Uncertain significance ★★ ⚠ same type
CLPP p.Arg174Cys 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/clpp-p-ile115phe (accessed [today's date]).

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