Is CPXM2 p.Val239Ala (c.716T>C) pathogenic?

CPXM2 p.Val239Ala (c.716T>C) is classified Uncertain significance in CPXM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely benign (0.1765); Very rare (popmax 0.000169%, nfe).

How common is CPXM2 p.Val239Ala (c.716T>C) in the general population?

CPXM2 p.Val239Ala (c.716T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CPXM2 p.Val239Ala (c.716T>C)?

AlphaMissense predicts likely benign (score 0.1765) — an in-silico prediction, not a clinical call.

CPXM2 p.Val239Ala

c.716T>C · VCV3496716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1765	likely benign
REVEL	0.456	indeterminate
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP -0.17, phastCons 0.93
Regional constraint	o/e 0.92	unconstrained · MANE · 145 kb · p 0.015 · regional, not allelic
Overall
CADD	20.3	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 0.000169% European (non-Finnish) · 2/1,180,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,822 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.Val239Ala
Coding: c.716T>C
MANE Select: NM_198148
Type: single nucleotide variant
Location: chr10:123799137 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.58
Residue 239: 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 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
CPXM2 p.Ala402Val Uncertain significance ★ ⚠ same type
CPXM2 p.Ala524Ser 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-val239ala (accessed [today's date]).

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