# NM_001386140.1(MTTP):c.1275A>G (p.Arg425=)

https://sugi.bio/variant/mttp-p-arg425

## Summary

**MTTP p.Arg425= (c.1275A>G)** is classified **Likely benign** in MTTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-13). Very rare (popmax 0.00144%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1272181497 · 2 submitters · very rare (popmax 0.00144%, nfe)

## For patients & families {#patients}

This is a change in the MTTP gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Arg425= |
| Coding change (HGVS c.) | c.1275A>G |
| MANE Select transcript | [NM_001386140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386140) |
| dbSNP | [rs1272181497](https://www.ncbi.nlm.nih.gov/snp/rs1272181497/) |
| Variant type | single nucleotide variant |
| Location | chr4:99601645-99601645 (GRCh38) |
| ClinVar | [VCV1131584](https://www.ncbi.nlm.nih.gov/clinvar/variation/1131584/) |

**All HGVS expressions:** `NC_000004.11:g.100522802A>G`, `NC_000004.12:g.99601645A>G`, `NG_011469.1:g.42563A>G`, `NM_000253.4:c.1275A>G`, `NM_001300785.2:c.1026A>G`, `NM_001386140.1:c.1275A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.493, GERP 1.77, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.192**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 38 bp away.
- 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 (gnomAD v4.1): grpmax **0.00144%** (nfe) · FAF95 0.000878% · FAF99 0.000718% · 17/1,179,272 in the highest group · 19/1,612,990 alleles overall — very rare (popmax 0.00144%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,218 |
| European (non-Finnish) (grpmax) | 0.00144% | 69,369 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **425** 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.Arg425= 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-13.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-04-16 |

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

## 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.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), [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 1131584). 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.*