# NM_005021.5(ENPP3):c.542T>A (p.Met181Lys)

https://sugi.bio/variant/enpp3-p-met181lys

## Summary

**ENPP3 p.Met181Lys (c.542T>A)** is classified **Uncertain significance** in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.6332); Ultra-rare (popmax 0.0493%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0493%, eas)

## For patients & families {#patients}

This is a change in the ENPP3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ENPP3](https://sugi.bio/atlas/gene/ENPP3/) |
| Protein change (HGVS p.) | p.Met181Lys |
| Coding change (HGVS c.) | c.542T>A |
| MANE Select transcript | [NM_005021](https://www.ncbi.nlm.nih.gov/nuccore/NM_005021) |
| Variant type | single nucleotide variant |
| Location | chr6:131658400-131658400 (GRCh38) |
| ClinVar | [VCV3275488](https://www.ncbi.nlm.nih.gov/clinvar/variation/3275488/) |

**All HGVS expressions:** `NC_000006.11:g.131979540T>A`, `NC_000006.12:g.131658400T>A`, `NG_033982.1:g.26099T>A`, `NM_005021.5:c.542T>A`, `NR_133007.2:n.625T>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6332)
- REVEL 0.513 (indeterminate)
- SaProt LLR -9.59 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 6.136, GERP 6.06, phastCons 0.996 — highly conserved (agrees)
- CADD: **PHRED 23.5**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (131,637,385–131,746,953), spanning 109,568 bp. Chi-square p 0.42. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.27 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0493%** (eas) · FAF95 0.0333% · FAF99 0.0281% · 22/44,626 in the highest group · 27/1,567,534 alleles overall — ultra-rare (popmax 0.0493%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0493% | 2,028 |
| Remaining individuals (not grpmax-eligible) | 0.00492% | 20,305 |
| South Asian | 0.00111% | 89,982 |
| European (non-Finnish) | 8.79e-05% | 1,137,826 |

*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}

**ENPP3** population constraint: LOEUF 1.211, pLI 2.0771e-15, missense-Z 0.51033. *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 **181** lies in a disulfide bond; the 'phosphodiesterase' region.

AlphaFold model confidence (whole protein): pLDDT 95.50, 93% of residues very-high.

**3 experimental structure(s)** (PDB): [6C01](https://www.rcsb.org/structure/6C01), [6C02](https://www.rcsb.org/structure/6C02), [9NIR](https://www.rcsb.org/structure/9NIR).

## What this gene does {#gene-function}

*Describes the biological roles of ENPP3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ENPP3's established molecular role includes bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity. p.Met181Lys falls in the phosphodiesterase region.


### Pathways affected {#pathways}

ENPP3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Vitamin B5 (pantothenate) metabolism](https://reactome.org/content/detail/R-HSA-199220) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity, phosphodiesterase I activity, calcium ion binding, zinc ion binding, bis(5'-adenosyl)-pentaphosphatase activity, nucleoside triphosphate diphosphatase activity.

**Biological process:** pyrimidine nucleotide metabolic process, phosphate-containing compound metabolic process, nucleoside triphosphate catabolic process, ATP metabolic process, negative regulation of cGAS/STING signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-12 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ENPP3 variant pages (same residue, condition, or type): [OR2A4 p.Leu181Val](/variant/or2a4-p-leu181val), [ENPP3 c.762+4T>C](/variant/enpp3-c-762-plus-4t-c), [CTAGE9 p.Ala668Thr](/variant/ctage9-p-ala668thr), [CTAGE9 p.Asp478Tyr](/variant/ctage9-p-asp478tyr), [CTAGE9 p.Glu332Lys](/variant/ctage9-p-glu332lys), [CTAGE9 p.Glu414Asp](/variant/ctage9-p-glu414asp), [CTAGE9 p.Ile207Thr](/variant/ctage9-p-ile207thr), [ENPP3 p.Ala248Asp](/variant/enpp3-p-ala248asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 3275488). 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.*