# NM_001386140.1(MTTP):c.1023A>G (p.Lys341=)

https://sugi.bio/variant/mttp-p-lys341

## Summary

**MTTP p.Lys341= (c.1023A>G)** is classified **Conflicting classifications of pathogenicity** in MTTP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-29). Rare (popmax 0.215%, mid); Associated with abetalipoproteinemia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs145724674 · 7 submitters · 1 linked condition · rare (popmax 0.215%, mid)

## 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 7 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.Lys341= |
| Coding change (HGVS c.) | c.1023A>G |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| dbSNP | [rs145724674](https://www.ncbi.nlm.nih.gov/snp/rs145724674/) |
| Variant type | single nucleotide variant |
| Location | chr4:99597180-99597180 (GRCh38) |
| ClinVar | [VCV347033](https://www.ncbi.nlm.nih.gov/clinvar/variation/347033/) |

**All HGVS expressions:** `NC_000004.11:g.100518337A>G`, `NC_000004.12:g.99597180A>G`, `NG_011469.1:g.38098A>G`, `NM_000253.4:c.1023A>G`, `NM_001300785.2:c.774A>G`, `NM_001386140.1:c.1023A>G`

## 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 2.003, GERP -0.865, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 6.988**. 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: **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 **0.215%** (mid) · FAF95 0.127% · FAF99 0.101% · 13/6,058 in the highest group · 231/1,614,030 alleles overall — rare (popmax 0.215%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.215% | 466 |
| African / African-American | 0.076% | 1,316 |
| Admixed American | 0.0283% | 3,530 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,251 |
| European (non-Finnish) | 0.0106% | 9,439 |
| South Asian | 0.00659% | 15,181 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,339 |

*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 **341** lies in the vitellogenin domain; an α-helix.

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.Lys341= 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 2026-01-29.

**Submitter consensus:** conflicting (4 Likely benign, 2 Uncertain significance, 1 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-12 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-11-11 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Abetalipoproteinaemia, not provided, not specified, AllHighlyPenetrant, none provided, 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 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), [MTTP c.502-2A>G](/variant/mttp-c-502-minus-2a-g).

### 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 347033). 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.*