Is CPXM2 p.Arg158Cys (c.472C>T) pathogenic?

CPXM2 p.Arg158Cys (c.472C>T) is classified Uncertain significance in CPXM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). AlphaMissense: ambiguous (0.5374); Very rare (popmax 0.00347%, nfe).

How common is CPXM2 p.Arg158Cys (c.472C>T) in the general population?

CPXM2 p.Arg158Cys (c.472C>T) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about CPXM2 p.Arg158Cys (c.472C>T)?

AlphaMissense predicts ambiguous (score 0.5374) — an in-silico prediction, not a clinical call.

CPXM2 p.Arg158Cys

c.472C>T · VCV3836074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5374	ambiguous
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -9.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 145 kb · p 0.015 · regional, not allelic
Overall
CADD	33.0	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 0.00347% European (non-Finnish) · 41/1,180,050 alleles

Filtering AF 0.00258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00254% 41/1,614,042 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: CPXM2
Protein: p.Arg158Cys
Coding: c.472C>T
MANE Select: NM_198148
Type: single nucleotide variant
Location: chr10:123862655 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.58
Residue 158: a disulfide bond; the f5/8 type c domain

Full CPXM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPXM2 p.Arg158His Uncertain significance ★ ⚠ same residue
CPXM2 p.Arg158Leu Uncertain significance ★ ⚠ same residue
CPXM2 c.1918-10T>C Benign ★★ same type
CPXM2 p.Ala172= Benign ★★ same type
CPXM2 p.Lys577Arg Benign ★★ same type
CPXM2 p.Ala153Asp Uncertain significance ★ ⚠ same type
CPXM2 p.Ala183Val Uncertain significance ★ ⚠ same type
CPXM2 p.Ala376Val 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/cpxm2-p-arg158cys (accessed [today's date]).

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