# NM_001386140.1(MTTP):c.507T>C (p.Asp169=)

https://sugi.bio/variant/mttp-p-asp169

## Summary

**MTTP p.Asp169= (c.507T>C)** is classified **Likely benign** in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-03). Very rare (popmax 0.00268%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs1388191865 · 1 submitter · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the MTTP gene that is classified as likely benign — not considered disease-causing, 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 | [MTTP](https://sugi.bio/atlas/gene/MTTP/) |
| Protein change (HGVS p.) | p.Asp169= |
| Coding change (HGVS c.) | c.507T>C |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| dbSNP | [rs1388191865](https://www.ncbi.nlm.nih.gov/snp/rs1388191865/) |
| Variant type | single nucleotide variant |
| Location | chr4:99591240-99591240 (GRCh38) |
| ClinVar | [VCV2804178](https://www.ncbi.nlm.nih.gov/clinvar/variation/2804178/) |

**All HGVS expressions:** `NC_000004.11:g.100512397T>C`, `NC_000004.12:g.99591240T>C`, `NG_011469.1:g.32158T>C`, `NM_000253.4:c.507T>C`, `NM_001300785.2:c.258T>C`, `NM_001386140.1:c.507T>C`

## 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 0.008, GERP -2.23, phastCons 0.872 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.038**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.37 acceptor loss), 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 **0.00268%** (afr) · FAF95 0.000445% · FAF99 0.000166% · 2/74,640 in the highest group · 3/1,605,420 alleles overall — very rare (popmax 0.00268%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00268% | 37,320 |
| European (non-Finnish) | 8.53e-05% | 1,172,374 |

*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 **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.Asp169= 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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-03 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **169** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MTTP p.Asp169Val](/variant/mttp-p-asp169val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MTTP variant pages (same residue, condition, or type): [MTTP p.Asp169Val](/variant/mttp-p-asp169val), [MTTP c.1067+1G>C](/variant/mttp-c-1067-plus-1g-c), [MTTP c.1236+1G>A](/variant/mttp-c-1236-plus-1g-a), [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).

### 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 2804178). 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.*