Is CLPX p.Val418Met (c.1252G>A) pathogenic?

CLPX p.Val418Met (c.1252G>A) is classified Uncertain significance in CLPX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). AlphaMissense: likely pathogenic (0.8021); Ultra-rare (popmax 0.0165%, mid).

How common is CLPX p.Val418Met (c.1252G>A) in the general population?

CLPX p.Val418Met (c.1252G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLPX p.Val418Met (c.1252G>A)?

AlphaMissense predicts likely pathogenic (score 0.8021) — an in-silico prediction, not a clinical call.

CLPX p.Val418Met

c.1252G>A · rs1306898547 · VCV3014712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8021	likely pathogenic
REVEL	0.402	indeterminate
SaProt	LLR -10.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 8.5e-14 · regional, not allelic
Overall
CADD	28.4	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 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000205% 3/1,461,798 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Finnishnot grpmax-eligible	0.00156%	64,044
South Asian	0.0011%	91,076

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.Val418Met
Coding: c.1252G>A
MANE Select: NM_006660
dbSNP: rs1306898547
Type: single nucleotide variant
Location: chr15:65155751 (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-val418met (accessed [today's date]).

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