Is MTTP p.Asn140fs (c.419dup) pathogenic?

MTTP p.Asn140fs (c.419dup) is classified Pathogenic in MTTP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0118%, nfe); Associated with MTTP-related disorder.

What condition is associated with MTTP p.Asn140fs (c.419dup)?

MTTP p.Asn140fs (c.419dup) is associated with MTTP-related disorder, abetalipoproteinemia (ClinVar).

How common is MTTP p.Asn140fs (c.419dup) in the general population?

MTTP p.Asn140fs (c.419dup) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

MTTP p.Asn140fs

c.419dup · rs762901763 · VCV1072850

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Conditions

MTTP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP -1.6, phastCons 0.97
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% European (non-Finnish) · 138/1,172,924 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00953%

Overall 0.00884% 142/1,605,574 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0118%	8,499
Remaining individualsnot grpmax-eligible	0.00483%	20,711
African / African-American	0.00134%	74,450

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MTTP
Protein: p.Asn140fs
Coding: c.419dup
MANE Select: NM_001386140
dbSNP: rs762901763
Type: Duplication
Location: chr4:99589664 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.73 · 2 PDB
Residue 140: the vitellogenin domain

Full MTTP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MTTP-related disorder

Also linked: abetalipoproteinemia

Similar variants

MTTP p.Asn140Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MTTP p.Glu134fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Ile547fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Glu443Ter Likely pathogenic ★ same condition
MTTP p.Leu26fs Likely pathogenic ★ same condition
MTTP p.Leu79fs Likely pathogenic ★ same condition
MTTP p.Ser861fs Likely pathogenic ★ same condition
MTTP p.Thr787fs Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mttp-p-asn140fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown