Is MTTP p.Leu411fs (c.1230_1231del) pathogenic?

MTTP p.Leu411fs (c.12301231del) is classified Pathogenic in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-07). Very rare (popmax 0.00017%, nfe).

How common is MTTP p.Leu411fs (c.1230_1231del) in the general population?

MTTP p.Leu411fs (c.1230_1231del) is very rare (popmax 0.00017%, nfe) (gnomAD).

MTTP p.Leu411fs

c.1230_1231del · rs1725675795 · VCV2766675

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

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 9 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3	GERP -0.87, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,658 alleles

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

Overall 0.000137% 2/1,461,332 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.Leu411fs
Coding: c.1230_1231del
MANE Select: NM_001386140
dbSNP: rs1725675795
Type: Deletion
Location: chr4:99600726 (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 411: the vitellogenin domain; an α-helix

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

Similar variants

MTTP p.Leu411= Likely benign ★★ same residue
MTTP p.Ala214fs Pathogenic ★★ same type
MTTP p.Asp224fs Pathogenic/Likely pathogenic ★★ same type
MTTP p.Glu462fs Likely pathogenic ★★ same type
MTTP p.Glu465fs Pathogenic/Likely pathogenic ★★ same type
MTTP p.Gly49fs Pathogenic/Likely pathogenic ★★ same type
MTTP p.Ile650fs Pathogenic/Likely pathogenic ★★ same type
MTTP p.Leu125fs Pathogenic/Likely pathogenic ★★ same type

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-leu411fs (accessed [today's date]).

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