Is CLPP p.Pro248Leu (c.743C>T) pathogenic?

CLPP p.Pro248Leu (c.743C>T) is classified Uncertain significance in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.8758); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLPP p.Pro248Leu (c.743C>T)?

CLPP p.Pro248Leu (c.743C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLPP p.Pro248Leu (c.743C>T) in the general population?

CLPP p.Pro248Leu (c.743C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about CLPP p.Pro248Leu (c.743C>T)?

AlphaMissense predicts likely pathogenic (score 0.8758) — an in-silico prediction, not a clinical call.

CLPP p.Pro248Leu

c.743C>T · VCV4230113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8758	likely pathogenic
REVEL	0.445	indeterminate
SaProt	LLR -7.64	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 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 6,803 bp · p 5e-05 · regional, not allelic
Overall
CADD	28.7	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 0.000509% European (non-Finnish) · 6/1,179,476 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,460,336 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.Pro248Leu
Coding: c.743C>T
MANE Select: NM_006012
Type: single nucleotide variant
Location: chr19:6368619 (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 248: the 'disordered' region

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

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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-pro248leu (accessed [today's date]).

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