# NM_001386140.1(MTTP):c.1874C>T (p.Pro625Leu)

https://sugi.bio/variant/mttp-p-pro625leu

## Summary

**MTTP p.Pro625Leu (c.1874C>T)** is classified **Conflicting classifications of pathogenicity** in MTTP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0886); Rare (popmax 0.136%, afr); Associated with abetalipoproteinemia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs146045390 · 5 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.136%, afr)

## For patients & families {#patients}

This is a change in the MTTP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Pro625Leu |
| Coding change (HGVS c.) | c.1874C>T |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| dbSNP | [rs146045390](https://www.ncbi.nlm.nih.gov/snp/rs146045390/) |
| Variant type | single nucleotide variant |
| Location | chr4:99611338-99611338 (GRCh38) |
| ClinVar | [VCV935777](https://www.ncbi.nlm.nih.gov/clinvar/variation/935777/) |

**All HGVS expressions:** `NC_000004.11:g.100532495C>T`, `NC_000004.12:g.99611338C>T`, `NG_011469.1:g.52256C>T`, `NM_000253.4:c.1874C>T`, `NM_001300785.2:c.1625C>T`, `NM_001386140.1:c.1874C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0886)
- REVEL 0.125 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.28 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.559, GERP 1.48, phastCons 0.929 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.49**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 acceptor gain), 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 **0.136%** (afr) · FAF95 0.115% · FAF99 0.107% · 102/74,968 in the highest group · 115/1,613,946 alleles overall — rare (popmax 0.136%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.136% | 735 |
| Admixed American | 0.01% | 10,000 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,417 |
| European (non-Finnish) | 8.48e-05% | 1,179,934 |

*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 **625** lies in 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.Pro625Leu 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-11.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-02-13 |
| New York Genome Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-03-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-11 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-09-23 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Abetalipoproteinaemia, not provided, MTTP-related disorder, not specified, MTTP-related condition, none provided, Abetalipoproteinemia, Abetalipoproteinemia neuropathy, Apolipoprotein B deficiency, Congenital betalipoprotein deficiency syndrome.

## Same-residue context {#hotspot}

Residue **625** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MTTP p.Pro625fs](/variant/mttp-p-pro625fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MTTP variant pages (same residue, condition, or type): [MTTP p.Pro625Ser](/variant/mttp-p-pro625ser), [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 2026-10-14); 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 935777). 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.*