# NM_001386140.1(MTTP):c.506A>T (p.Asp169Val)

https://sugi.bio/variant/mttp-p-asp169val

## Summary

**MTTP p.Asp169Val (c.506A>T)** is classified **Likely pathogenic** in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.9703); Absent from gnomAD v4.1; Associated with abetalipoproteinemia.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MTTP gene that is considered likely disease-causing, submitted by 1 submitter, 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.Asp169Val |
| Coding change (HGVS c.) | c.506A>T |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| Variant type | single nucleotide variant |
| Location | chr4:99591239-99591239 (GRCh38) |
| ClinVar | [VCV4817993](https://www.ncbi.nlm.nih.gov/clinvar/variation/4817993/) |

**All HGVS expressions:** `NC_000004.11:g.100512396A>T`, `NC_000004.12:g.99591239A>T`, `NG_011469.1:g.32157A>T`, `NM_000253.4:c.506A>T`, `NM_001300785.2:c.257A>T`, `NM_001386140.1:c.506A>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9703) — concordant with the pathogenic call
- REVEL 0.718 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.815 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.25) — consistent with the pathogenic call
- Conservation: phyloP 11.084, GERP 1.78, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 2%** most-pathogenic-predicted substitutions in MTTP (of 5,251 modeled).
- CADD: **PHRED 25.4**. 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 deltas (raw): acceptor loss **0.25**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **169** lies in a UniProt-annotated variant site (in abl; no loss on localization to the endoplasmic reticulum; does not reduce interaction with apob; inhibits interaction with p4hb/pdi; inhibits phospholipid or triglyceride transfer activity; inhibits apolipoprotein b secretion); the vitellogenin domain; a β-strand.

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.Asp169Val 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-06.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Abetalipoproteinaemia, MTP DEFICIENCY, Abetalipoproteinemia, Abetalipoproteinemia neuropathy, Apolipoprotein B deficiency, Congenital betalipoprotein deficiency syndrome.

## Similar variants {#similar}

Related MTTP variant pages (same residue, condition, or type): [MTTP p.Asp169=](/variant/mttp-p-asp169), [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 4817993). 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.*