Is CLPP p.Ala43Thr (c.127G>A) pathogenic?

CLPP p.Ala43Thr (c.127G>A) is classified Uncertain significance in CLPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-09). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.00426%, amr); Associated with Inborn genetic diseases.

What condition is associated with CLPP p.Ala43Thr (c.127G>A)?

CLPP p.Ala43Thr (c.127G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CLPP p.Ala43Thr (c.127G>A) in the general population?

CLPP p.Ala43Thr (c.127G>A) is very rare (popmax 0.00426%, amr) (gnomAD).

What do computational predictors say about CLPP p.Ala43Thr (c.127G>A)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

CLPP p.Ala43Thr

c.127G>A · rs1454742423 · VCV499916

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00426%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -6.76	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 1.9	GERP -0.3, phastCons 0.9
Regional constraint	o/e 1.21	unconstrained · MANE · 328 bp · p 0.022 · regional, not allelic
Overall
CADD	12.64	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 0.00426% Admixed American · 2/46,952 alleles

Filtering AF 0.000706% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000264%

Overall 0.000266% 4/1,501,388 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00426%	23,476
European (non-Finnish)	0.000177%	564,022

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.Ala43Thr
Coding: c.127G>A
MANE Select: NM_006012
dbSNP: rs1454742423
Type: single nucleotide variant
Location: chr19:6361701 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLPP p.Ala43Val Uncertain significance ★ ⚠ same residue
CLPP p.Ala10Ser Uncertain significance ★★ ⚠ same condition
CLPP p.Ala128Thr Uncertain significance ★★ ⚠ same condition
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-ala43thr (accessed [today's date]).

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