Is MTTP p.Ile650fs (c.1949del) pathogenic?

MTTP p.Ile650fs (c.1949del) is classified Pathogenic/Likely pathogenic in MTTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-28). Very rare (popmax 0.000169%, nfe); Associated with abetalipoproteinemia.

What condition is associated with MTTP p.Ile650fs (c.1949del)?

MTTP p.Ile650fs (c.1949del) is associated with abetalipoproteinemia (ClinVar).

How common is MTTP p.Ile650fs (c.1949del) in the general population?

MTTP p.Ile650fs (c.1949del) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Abetalipoproteinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MTTP p.Ile650fs

c.1949del · rs1725952378 · VCV1068931

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

abetalipoproteinemia

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 14 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.26	GERP -3, phastCons 0.52
Overall
CADD	34.0	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 0.000169% European (non-Finnish) · 2/1,179,972 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,016 alleles · very rare

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.Ile650fs
Coding: c.1949del
MANE Select: NM_001386140
dbSNP: rs1725952378
Type: Deletion
Location: chr4:99611413 (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 650: the vitellogenin domain; a β-strand

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

Disease context

abetalipoproteinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Abetalipoproteinemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

MTTP p.Ala214fs Pathogenic ★★ same condition
MTTP p.Asp224fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Glu462fs Likely pathogenic ★★ same condition
MTTP p.Glu465fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Gly49fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Leu125fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Phe399fs Pathogenic/Likely pathogenic ★★ same condition
MTTP p.Ser738fs Pathogenic/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-ile650fs (accessed [today's date]).

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