Is MTTP p.Thr37fs (c.109dup) pathogenic?

MTTP p.Thr37fs (c.109dup) is classified Pathogenic in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). Very rare (popmax 0.00133%, afr).

How common is MTTP p.Thr37fs (c.109dup) in the general population?

MTTP p.Thr37fs (c.109dup) is very rare (popmax 0.00133%, afr) (gnomAD).

MTTP p.Thr37fs

c.109dup · rs1725126993 · VCV2745785

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 2 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -1.1, phastCons 0.91
Overall
CADD	23.6	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 0.00133% African / African-American · 1/74,910 alleles

Overall 0.000657% 1/152,144 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.Thr37fs
Coding: c.109dup
MANE Select: NM_001386140
dbSNP: rs1725126993
Type: Duplication
Location: chr4:99581951 (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 37: the vitellogenin domain; a β-strand

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

Similar variants

MTTP p.Thr37Met Uncertain significance ★★ ⚠ same residue
MTTP p.Thr37= Likely benign ★ same residue
MTTP p.Asn140fs Pathogenic ★★ same type
MTTP p.Glu134fs Pathogenic/Likely pathogenic ★★ same type
MTTP p.Ile344fs Pathogenic ★★ same type
MTTP p.Ile547fs Pathogenic/Likely pathogenic ★★ same type
MTTP p.Ala5fs Likely pathogenic ★ same type
MTTP p.Asp634fs 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-thr37fs (accessed [today's date]).

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