Is CLPP p.Arg185Trp (c.553C>T) pathogenic?

CLPP p.Arg185Trp (c.553C>T) is classified Uncertain significance in CLPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-18). AlphaMissense: likely benign (0.2601); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CLPP p.Arg185Trp (c.553C>T)?

CLPP p.Arg185Trp (c.553C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLPP p.Arg185Trp (c.553C>T) in the general population?

CLPP p.Arg185Trp (c.553C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CLPP p.Arg185Trp (c.553C>T)?

AlphaMissense predicts likely benign (score 0.2601) — an in-silico prediction, not a clinical call.

CLPP p.Arg185Trp

c.553C>T · rs765186008 · VCV1929972

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2601 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2601	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP -1.4, phastCons 0.57
Regional constraint	o/e 0.76	unconstrained · MANE · 6,803 bp · p 5e-05 · regional, not allelic
Overall
CADD	24.4	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 0.0167% Admixed American · 10/59,824 alleles

Filtering AF 0.00902% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00683%

Overall 0.00131% 21/1,608,304 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,982
African / African-American	0.00267%	37,435
European (non-Finnish)	0.000764%	130,913

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.Arg185Trp
Coding: c.553C>T
MANE Select: NM_006012
dbSNP: rs765186008
Type: single nucleotide variant
Location: chr19:6364637 (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 185: a β-strand

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

CLPP p.Arg185Gln Uncertain significance ★ ⚠ same residue
CLPP p.Arg185Leu Uncertain significance ★ ⚠ same residue
CLPP p.Ala10Ser Uncertain significance ★★ ⚠ same condition
CLPP p.Ala128Thr Uncertain significance ★★ ⚠ same condition
CLPP p.Ala43Thr Uncertain significance ★★ ⚠ same condition
CLPP p.Ala50Thr Uncertain significance ★★ ⚠ same condition
CLPP p.Gly8Ala Uncertain significance ★★ ⚠ same condition
CLPP p.Ile208Val 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-arg185trp (accessed [today's date]).

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