Is MTTP p.Arg540Cys (c.1618C>T) pathogenic?

MTTP p.Arg540Cys (c.1618C>T) is classified Pathogenic/Likely pathogenic in MTTP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-29). AlphaMissense: likely pathogenic (0.7277); Ultra-rare (popmax 0.0164%, mid); Associated with abetalipoproteinemia.

What condition is associated with MTTP p.Arg540Cys (c.1618C>T)?

MTTP p.Arg540Cys (c.1618C>T) is associated with abetalipoproteinemia (ClinVar).

How common is MTTP p.Arg540Cys (c.1618C>T) in the general population?

MTTP p.Arg540Cys (c.1618C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Abetalipoproteinemia inherited?

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

What do computational predictors say about MTTP p.Arg540Cys (c.1618C>T)?

AlphaMissense predicts likely pathogenic (score 0.7277) — an in-silico prediction, not a clinical call.

MTTP p.Arg540Cys

c.1618C>T · rs372321643 · VCV840396

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

abetalipoproteinemia

Computational evidence

Protein change
AlphaMissense	0.7277	likely pathogenic ✓ concordant with ClinVar
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -11.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.0026% 42/1,613,958 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00667%	15,000
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00267%	37,455
European (non-Finnish)	0.00263%	38,064
South Asian	0.0022%	45,544

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.Arg540Cys
Coding: c.1618C>T
MANE Select: NM_001386140
dbSNP: rs372321643
Type: single nucleotide variant
Location: chr4:99608826 (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 540: a UniProt-annotated variant site (in abl; does not reduce interaction with p4hb/pdi and apob; inhibits triglyceride transfer activity); a UniProt-annotated variant site (in abl; no loss on localization to the endoplasmic reticulum; reduces interaction with p4hb/pdi; inhibits phospholipid or triglyceride transfer activity; inhibits apolipoprotein b secretion); the vitellogenin domain; an α-helix

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.Arg540His Pathogenic/Likely pathogenic ★★ same residue
MTTP c.1067+1G>C 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
MTTP c.1868-2A>G Likely pathogenic ★★ same condition
MTTP c.2342+1G>A Pathogenic ★★ same condition
MTTP c.502-1G>C 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-arg540cys (accessed [today's date]).

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