Is CLPP c.270+25C>T pathogenic?

CLPP c.270+25C>T is classified Benign in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-25). Ultra-rare (popmax 0.0285%, nfe).

How common is CLPP c.270+25C>T in the general population?

CLPP c.270+25C>T is ultra-rare (popmax 0.0285%, nfe) (gnomAD).

CLPP c.270+25C>T

rs543721407 · VCV1240961

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +25	near-intronic (+25 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.046	GERP -3.4, phastCons 0.005
Overall
CADD	8.126	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0285% European (non-Finnish) · 335/1,175,748 alleles

Filtering AF 0.026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.209% 3,326/1,591,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.93%	17
Remaining individualsnot grpmax-eligible	0.199%	504
European (non-Finnish)grpmax	0.0285%	3,510
South Asian	0.00553%	18,069
Admixed American	0.00168%	59,362
African / African-American	0.00134%	74,852

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.270+25C>T
MANE Select: NM_006012
dbSNP: rs543721407
Type: single nucleotide variant
Location: chr19:6361965 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 32 PDB

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-c-270-plus-25c-t (accessed [today's date]).

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