Is CLPP p.Val264Ala (c.791T>C) pathogenic?

CLPP p.Val264Ala (c.791T>C) is classified Uncertain significance in CLPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely benign (0.0543); Ultra-rare (popmax 0.027%, afr); Associated with Perrault syndrome 3.

What condition is associated with CLPP p.Val264Ala (c.791T>C)?

CLPP p.Val264Ala (c.791T>C) is associated with Perrault syndrome 3 (ClinVar).

How common is CLPP p.Val264Ala (c.791T>C) in the general population?

CLPP p.Val264Ala (c.791T>C) is ultra-rare (popmax 0.027%, afr) (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.Val264Ala (c.791T>C)?

AlphaMissense predicts likely benign (score 0.0543) — an in-silico prediction, not a clinical call.

CLPP p.Val264Ala

c.791T>C · rs112719208 · VCV2063969

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.027%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Perrault syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0543	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.84	GERP -4
Regional constraint	o/e 0.76	unconstrained · MANE · 6,803 bp · p 5e-05 · regional, not allelic
Overall
CADD	0.135	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.027% African / African-American · 20/74,088 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00215% 34/1,583,596 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.027%	3,704
Remaining individualsnot grpmax-eligible	0.0212%	4,721
Admixed American	0.00182%	55,088

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.Val264Ala
Coding: c.791T>C
MANE Select: NM_006012
dbSNP: rs112719208
Type: single nucleotide variant
Location: chr19:6368667 (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 264: the 'disordered' region

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 c.368-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLPP p.Arg174Cys 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
CLPP p.Asp134His Likely pathogenic ★ same condition
CLPP p.Glu221Ter 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-val264ala (accessed [today's date]).

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