Is MTTP p.Ala214fs (c.640del) pathogenic?

MTTP p.Ala214fs (c.640del) is classified Pathogenic in MTTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-08). Very rare (popmax 0.0011%, sas); Associated with MTTP-related disorder.

What condition is associated with MTTP p.Ala214fs (c.640del)?

MTTP p.Ala214fs (c.640del) is associated with MTTP-related disorder, abetalipoproteinemia (ClinVar).

How common is MTTP p.Ala214fs (c.640del) in the general population?

MTTP p.Ala214fs (c.640del) is very rare (popmax 0.0011%, sas) (gnomAD).

MTTP p.Ala214fs

c.640del · rs2110218614 · VCV1687508

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 6 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP 0.71, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,988 alleles

Overall 6.85e-05% 1/1,460,584 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.Ala214fs
Coding: c.640del
MANE Select: NM_001386140
dbSNP: rs2110218614
Type: Deletion
Location: chr4:99591672 (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 214: 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.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.Ile650fs 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-ala214fs (accessed [today's date]).

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