# NM_198148.3(CPXM2):c.516G>A (p.Ala172=)

https://sugi.bio/variant/cpxm2-p-ala172

## Summary

**CPXM2 p.Ala172= (c.516G>A)** is classified **Benign** in CPXM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2017-08-08). Low-frequency (popmax 2.07%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs138633933 · 3 submitters · low-frequency (popmax 2.07%, afr)

## For patients & families {#patients}

This is a change in the CPXM2 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPXM2](https://sugi.bio/atlas/gene/CPXM2/) |
| Protein change (HGVS p.) | p.Ala172= |
| Coding change (HGVS c.) | c.516G>A |
| MANE Select transcript | [NM_198148](https://www.ncbi.nlm.nih.gov/nuccore/NM_198148) |
| dbSNP | [rs138633933](https://www.ncbi.nlm.nih.gov/snp/rs138633933/) |
| Variant type | single nucleotide variant |
| Location | chr10:123842486-123842486 (GRCh38) |
| ClinVar | [VCV787082](https://www.ncbi.nlm.nih.gov/clinvar/variation/787082/) |

**All HGVS expressions:** `NC_000010.10:g.125602002C>T`, `NC_000010.11:g.123842486C>T`, `NG_052814.1:g.106609G>A`, `NM_198148.3:c.516G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.57) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.283, GERP -5.12 — fast-evolving / accelerated position
- CADD: **PHRED 15.25**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.57**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.57**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **2.07%** (afr) · FAF95 1.98% · FAF99 1.95% · 1,551/74,986 in the highest group · 1,712/1,613,898 alleles overall — low-frequency (popmax 2.07%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.07% | 48 |
| Remaining individuals (not grpmax-eligible) | 0.112% | 893 |
| Admixed American | 0.0867% | 1,154 |
| Middle Eastern | 0.033% | 3,031 |
| European (non-Finnish) | 0.00297% | 33,711 |
| South Asian | 0.0022% | 45,532 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CPXM2** population constraint: LOEUF 0.974, pLI 2.5542e-15, missense-Z 0.8142. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **172** lies in a disulfide bond; the f5/8 type c domain.

AlphaFold model confidence (whole protein): pLDDT 82.58, 67% of residues very-high.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2017-08-08.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 5 submissions (2017); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2017-08-08 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, Malignant tumor of esophagus, Uterine corpus endometrial carcinoma, Clear cell carcinoma of kidney, none provided.

## Similar variants {#similar}

Related CPXM2 variant pages (same residue, condition, or type): [CPXM2 c.1918-10T>C](/variant/cpxm2-c-1918-minus-10t-c), [CPXM2 p.Lys577Arg](/variant/cpxm2-p-lys577arg), [CPXM2 p.Ala153Asp](/variant/cpxm2-p-ala153asp), [CPXM2 p.Ala183Val](/variant/cpxm2-p-ala183val), [CPXM2 p.Ala376Val](/variant/cpxm2-p-ala376val), [CPXM2 p.Ala402Val](/variant/cpxm2-p-ala402val), [CPXM2 p.Ala524Ser](/variant/cpxm2-p-ala524ser), [CPXM2 p.Ala565Asp](/variant/cpxm2-p-ala565asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 787082). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*