# NM_001386140.1(MTTP):c.1151A>C (p.Asp384Ala)

https://sugi.bio/variant/mttp-p-asp384ala

## Summary

**MTTP p.Asp384Ala (c.1151A>C)** is classified **Benign/Likely benign** in MTTP (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0965); Common (popmax 15.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with abetalipoproteinemia.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs17029215 · 10 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 15.7%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the MTTP gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 submitters, and is linked to abetalipoproteinemia.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MTTP is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Abetalipoproteinemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Acanthocytosis — Very frequent (99-80%)
- Steatorrhea — Very frequent (99-80%)
- Fat malabsorption — Very frequent (99-80%)
- Abnormal circulating apolipoprotein concentration — Very frequent (99-80%)
- Low levels of vitamin E — Very frequent (99-80%)
- Progressive visual loss — Frequent (79-30%)
- Color vision defect — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000005/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MTTP](https://sugi.bio/atlas/gene/MTTP/) |
| Protein change (HGVS p.) | p.Asp384Ala |
| Coding change (HGVS c.) | c.1151A>C |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| dbSNP | [rs17029215](https://www.ncbi.nlm.nih.gov/snp/rs17029215/) |
| Variant type | single nucleotide variant |
| Location | chr4:99600648-99600648 (GRCh38) |
| ClinVar | [VCV283193](https://www.ncbi.nlm.nih.gov/clinvar/variation/283193/) |

**All HGVS expressions:** `NC_000004.11:g.100521805A>C`, `NC_000004.12:g.99600648A>C`, `NG_011469.1:g.41566A>C`, `NM_000253.4:c.1151A>C`, `NM_001300785.2:c.902A>C`, `NM_001386140.1:c.1151A>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 15.7%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0965)
- REVEL 0.048 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.495 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.355, GERP -2.47, phastCons 0.006 — weakly conserved position
- CADD: **PHRED 11.69**. 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 0.89** across the covering region of the MANE Select transcript (99,574,910–99,622,845), spanning 47,935 bp. Chi-square p 0.00018. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **15.7%** (afr) · FAF95 15.4% · FAF99 15.3% · 11,753/74,982 in the highest group · 72,935/1,613,764 alleles overall — common (popmax 15.7%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 15.7% | 6 |
| Ashkenazi Jewish (not grpmax-eligible) | 5.2% | 19 |
| Finnish (not grpmax-eligible) | 5.16% | 19 |
| Remaining individuals (not grpmax-eligible) | 4.94% | 20 |
| Middle Eastern | 4.66% | 21 |
| European (non-Finnish) | 4.06% | 25 |
| Admixed American | 3.85% | 26 |
| South Asian | 3.03% | 33 |
| Amish (not grpmax-eligible) | 0.11% | 910 |
| East Asian | 0.00669% | 14,954 |

*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}

**MTTP** population constraint: LOEUF 0.672, pLI 6.7227e-07, missense-Z 1.9465; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 **384** lies in a UniProt-annotated variant site (no loss on localization to the endoplasmic reticulum; does not reduce interaction with p4hb/pdi; reduces phospholipid or triglyceride transfer activity; does not inhibit apolipoprotein b secretion); the vitellogenin domain.

AlphaFold model confidence (whole protein): pLDDT 86.73, 56% of residues very-high.

**2 experimental structure(s)** (PDB): [6I7S](https://www.rcsb.org/structure/6I7S), [8EOJ](https://www.rcsb.org/structure/8EOJ).

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

*Describes the biological roles of MTTP (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:** MTTP's established molecular role includes protein heterodimerization activity. p.Asp384Ala falls in the vitellogenin domain.


### Pathways affected {#pathways}

MTTP participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chylomicron assembly](https://reactome.org/content/detail/R-HSA-8963888) | curated |
| [LDL remodeling](https://reactome.org/content/detail/R-HSA-8964041) | curated |
| [VLDL assembly](https://reactome.org/content/detail/R-HSA-8866423) | curated |

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

**Molecular function:** protein heterodimerization activity, phospholipid transfer activity, phosphatidylcholine transfer activity, cholesterol transfer activity, triglyceride transfer activity, ceramide 1-phosphate transfer activity.

**Biological process:** protein secretion, phospholipid transport, triglyceride transport, plasma lipoprotein particle assembly.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (8 Benign, 2 Likely benign).

**Submission history:** 10 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-10 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2019-10-31 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-09-21 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-09-22 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2025-01-14 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[abetalipoproteinemia](https://sugi.bio/atlas/disease/abetalipoproteinemia/).

**Reported phenotype names (ClinVar):** Abetalipoproteinaemia, not specified, not provided, AllHighlyPenetrant, none provided, Abetalipoproteinemia, Abetalipoproteinemia neuropathy, Apolipoprotein B deficiency, Congenital betalipoprotein deficiency syndrome, MTP DEFICIENCY.

## Similar variants {#similar}

Related MTTP variant pages (same residue, condition, or type): [MTTP p.Asp384Asn](/variant/mttp-p-asp384asn), [MTTP c.1067+1G>C](/variant/mttp-c-1067-plus-1g-c), [MTTP c.1769+2T>C](/variant/mttp-c-1769-plus-2t-c), [MTTP c.1867+1G>A](/variant/mttp-c-1867-plus-1g-a), [MTTP c.1867+5G>A](/variant/mttp-c-1867-plus-5g-a), [MTTP c.1868-2A>G](/variant/mttp-c-1868-minus-2a-g), [MTTP c.2342+1G>A](/variant/mttp-c-2342-plus-1g-a), [MTTP c.502-1G>C](/variant/mttp-c-502-minus-1g-c).

### 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 2026-10-14); 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 283193). 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.*