Is CLPX p.Thr8Ala (c.22A>G) pathogenic?

CLPX p.Thr8Ala (c.22A>G) is classified Uncertain significance in CLPX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-01). AlphaMissense: likely benign (0.0611); Very rare (popmax 0.00567%, amr).

How common is CLPX p.Thr8Ala (c.22A>G) in the general population?

CLPX p.Thr8Ala (c.22A>G) is very rare (popmax 0.00567%, amr) (gnomAD).

What do computational predictors say about CLPX p.Thr8Ala (c.22A>G)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

CLPX p.Thr8Ala

c.22A>G · rs751757923 · VCV1925338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00567%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.47	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 4.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 6,149 bp · p 4.1e-05 · regional, not allelic
Overall
CADD	19.58	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 0.00567% Admixed American · 3/52,922 alleles

Filtering AF 0.0015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000817%

Overall 0.00105% 15/1,424,040 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00567%	17,641
European (non-Finnish)	0.00103%	96,778

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: CLPX
Protein: p.Thr8Ala
Coding: c.22A>G
MANE Select: NM_006660
dbSNP: rs751757923
Type: single nucleotide variant
Location: chr15:65185132 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 67.22 · 3 PDB

Full CLPX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLPX p.Ala13Val Uncertain significance ★★ ⚠ same type
CLPX p.Ala65Ser Uncertain significance ★★ ⚠ same type
CLPX p.Arg270Gln Uncertain significance ★★ ⚠ same type
CLPX p.Asn424Ser Uncertain significance ★★ ⚠ same type
CLPX p.Gln352His Uncertain significance ★★ ⚠ same type
CLPX p.Gln47Arg Uncertain significance ★★ ⚠ same type
CLPX p.Glu539Lys Uncertain significance ★★ ⚠ same type
CLPX p.Glu614Gly 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/clpx-p-thr8ala (accessed [today's date]).

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