Is MTTP p.Arg595Ter (c.1783C>T) pathogenic?

MTTP p.Arg595Ter (c.1783C>T) is classified Pathogenic in MTTP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-17). Very rare (popmax 0.000339%, nfe); Associated with MTTP-related disorder.

What condition is associated with MTTP p.Arg595Ter (c.1783C>T)?

MTTP p.Arg595Ter (c.1783C>T) is associated with MTTP-related disorder, abetalipoproteinemia (ClinVar).

How common is MTTP p.Arg595Ter (c.1783C>T) in the general population?

MTTP p.Arg595Ter (c.1783C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

MTTP p.Arg595Ter

c.1783C>T · rs199422219 · VCV14235

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

MTTP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	loss · gain 0.05 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4	GERP 0.79, phastCons 0.89
Overall
CADD	39.0	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 0.000339% European (non-Finnish) · 4/1,179,874 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,534 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.Arg595Ter
Coding: c.1783C>T
MANE Select: NM_001386140
dbSNP: rs199422219
Type: single nucleotide variant
Location: chr4:99611156 (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 595: the vitellogenin domain; an α-helix

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.Arg595Gln Uncertain significance ★★ ⚠ same residue
MTTP p.Arg595Pro Uncertain significance ★ ⚠ same residue
MTTP p.Arg595= Likely benign ★ same residue
MTTP c.1067+1G>C Likely pathogenic ★★ same condition
MTTP c.1236+1G>A Pathogenic/Likely pathogenic ★★ same condition
MTTP c.1769+2T>C Pathogenic/Likely pathogenic ★★ same condition
MTTP c.1867+1G>A Pathogenic ★★ same condition
MTTP c.1867+5G>A 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-arg595ter (accessed [today's date]).

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