# NM_001386140.1(MTTP):c.1197del (p.Phe399fs)

https://sugi.bio/variant/mttp-p-phe399fs

## Summary

**MTTP p.Phe399fs (c.1197del)** is classified **Pathogenic/Likely pathogenic** in MTTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-05). Very rare (popmax 0.00017%, nfe); Associated with abetalipoproteinemia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1350615652 · 2 submitters · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the MTTP gene that is considered likely disease-causing, submitted by 2 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.Phe399fs |
| Coding change (HGVS c.) | c.1197del |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| dbSNP | [rs1350615652](https://www.ncbi.nlm.nih.gov/snp/rs1350615652/) |
| Variant type | Deletion |
| Location | chr4:99600692-99600692 (GRCh38) |
| ClinVar | [VCV2999044](https://www.ncbi.nlm.nih.gov/clinvar/variation/2999044/) |

**All HGVS expressions:** `NC_000004.11:g.100521851del`, `NC_000004.12:g.99600694del`, `NG_011469.1:g.41612del`, `NM_000253.3:c.1197delT`, `NM_000253.4:c.1197del`, `NM_001300785.2:c.948del`, `NM_001386140.1:c.1197del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -0.277, GERP -2.53, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.672, pLI 6.7227e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 18**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,816 in the highest group · 2/1,613,804 alleles overall — very rare (popmax 0.00017%, nfe).

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **399** lies in 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.Phe399fs 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-05.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-25 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-05 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related MTTP variant pages (same residue, condition, or type): [MTTP p.Ala214fs](/variant/mttp-p-ala214fs), [MTTP p.Asp224fs](/variant/mttp-p-asp224fs), [MTTP p.Glu462fs](/variant/mttp-p-glu462fs), [MTTP p.Glu465fs](/variant/mttp-p-glu465fs), [MTTP p.Gly49fs](/variant/mttp-p-gly49fs), [MTTP p.Ile650fs](/variant/mttp-p-ile650fs), [MTTP p.Leu125fs](/variant/mttp-p-leu125fs), [MTTP p.Ser738fs](/variant/mttp-p-ser738fs).

### 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 2999044). 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.*