# NM_001039396.2(MPEG1):c.1401C>T (p.Ala467=)

https://sugi.bio/variant/mpeg1-p-ala467

## Summary

**MPEG1 p.Ala467= (c.1401C>T)** is classified **Benign** in MPEG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-16). Low-frequency (popmax 1.28%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs183721976 · 2 submitters · low-frequency (popmax 1.28%, afr)

## For patients & families {#patients}

This is a change in the MPEG1 gene that is classified as benign — not considered disease-causing, submitted by 2 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 | [MPEG1](https://sugi.bio/atlas/gene/MPEG1/) |
| Protein change (HGVS p.) | p.Ala467= |
| Coding change (HGVS c.) | c.1401C>T |
| MANE Select transcript | [NM_001039396](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039396) |
| dbSNP | [rs183721976](https://www.ncbi.nlm.nih.gov/snp/rs183721976/) |
| Variant type | single nucleotide variant |
| Location | chr11:59211465-59211465 (GRCh38) |
| ClinVar | [VCV716949](https://www.ncbi.nlm.nih.gov/clinvar/variation/716949/) |

**All HGVS expressions:** `NC_000011.10:g.59211465G>A`, `NC_000011.9:g.58978938G>A`, `NM_001039396.2:c.1401C>T`

## Computational & population evidence {#evidence}

- CADD: **PHRED 0.582**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.28%** (afr) · FAF95 1.21% · FAF99 1.19% · 962/75,048 in the highest group · 1,157/1,614,180 alleles overall — low-frequency (popmax 1.28%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.28% | 78 |
| Middle Eastern | 0.165% | 606 |
| Admixed American | 0.117% | 858 |
| Remaining individuals (not grpmax-eligible) | 0.107% | 933 |
| European (non-Finnish) | 0.0039% | 25,653 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| South Asian | 0.0011% | 91,080 |

*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}

**MPEG1** population constraint: LOEUF 1.941, pLI 0.01968, missense-Z 0.5419. *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 **467** lies in a UniProt-annotated variant site (in imd77; decreased defense response to bacterium); a UniProt-annotated variant site (in); the 'p2' region.

AlphaFold model confidence (whole protein): pLDDT 83.22, 54% of residues very-high.

**5 experimental structure(s)** (PDB): [6U23](https://www.rcsb.org/structure/6U23), [6U2J](https://www.rcsb.org/structure/6U2J), [6U2K](https://www.rcsb.org/structure/6U2K), [6U2L](https://www.rcsb.org/structure/6U2L), [6U2W](https://www.rcsb.org/structure/6U2W).

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

*Describes the biological roles of MPEG1 (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:** MPEG1's established molecular role includes wide pore channel activity. p.Ala467= falls in the p2 region.


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

**Molecular function:** wide pore channel activity.

**Biological process:** defense response to bacterium, defense response to Gram-negative bacterium, defense response to Gram-positive bacterium.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-04-16.

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

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-04-16 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related MPEG1 variant pages (same residue, condition, or type): [MPEG1 p.Ala525Val](/variant/mpeg1-p-ala525val), [MPEG1 p.Gln259Glu](/variant/mpeg1-p-gln259glu), [MPEG1 p.Gln713Arg](/variant/mpeg1-p-gln713arg), [MPEG1 p.His420Tyr](/variant/mpeg1-p-his420tyr), [MPEG1 p.Thr73Ala](/variant/mpeg1-p-thr73ala), [MPEG1 p.Ala238Thr](/variant/mpeg1-p-ala238thr), [MPEG1 p.Ala238Val](/variant/mpeg1-p-ala238val), [MPEG1 p.Ala240Val](/variant/mpeg1-p-ala240val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 716949). 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.*