Is CLPX p.Arg373Trp (c.1117C>T) pathogenic?

CLPX p.Arg373Trp (c.1117C>T) is classified Uncertain significance in CLPX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-05). AlphaMissense: likely pathogenic (0.9976); Very rare (popmax 0.000593%, nfe).

How common is CLPX p.Arg373Trp (c.1117C>T) in the general population?

CLPX p.Arg373Trp (c.1117C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about CLPX p.Arg373Trp (c.1117C>T)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

CLPX p.Arg373Trp

c.1117C>T · rs759705385 · VCV2961725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic
REVEL	0.586	indeterminate
SaProt	LLR -14.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.28	donor loss, 36 bp away · masked 0 · deltas
Pangolin	Δ0.33	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 8.5e-14 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000593% European (non-Finnish) · 7/1,179,482 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,460,878 alleles · very rare

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.Arg373Trp
Coding: c.1117C>T
MANE Select: NM_006660
dbSNP: rs759705385
Type: single nucleotide variant
Location: chr15:65156873 (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

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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-arg373trp (accessed [today's date]).

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