Is MTTP p.Arg540His (c.1619G>A) pathogenic?

MTTP p.Arg540His (c.1619G>A) is classified Pathogenic/Likely pathogenic in MTTP (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-11-10). AlphaMissense: likely pathogenic (0.8109); Very rare (popmax 0.00517%, nfe); Associated with MTTP-related disorder.

What condition is associated with MTTP p.Arg540His (c.1619G>A)?

MTTP p.Arg540His (c.1619G>A) is associated with MTTP-related disorder, abetalipoproteinemia (ClinVar).

How common is MTTP p.Arg540His (c.1619G>A) in the general population?

MTTP p.Arg540His (c.1619G>A) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about MTTP p.Arg540His (c.1619G>A)?

AlphaMissense predicts likely pathogenic (score 0.8109) — an in-silico prediction, not a clinical call.

MTTP p.Arg540His

c.1619G>A · rs199422220 · VCV14238

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.8109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MTTP-related disorder

Computational evidence

Protein change
AlphaMissense	0.8109	likely pathogenic ✓ concordant with ClinVar
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -10.81	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	29.9	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 0.00517% European (non-Finnish) · 61/1,179,994 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00409% 66/1,613,968 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,344
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,450
Admixed American	0.00167%	59,990

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.Arg540His
Coding: c.1619G>A
MANE Select: NM_001386140
dbSNP: rs199422220
Type: single nucleotide variant
Location: chr4:99608827 (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

MTTP-related disorder

Also linked: abetalipoproteinemia

Similar variants

MTTP p.Arg540Cys Pathogenic/Likely pathogenic ★★ 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
MTTP c.1868-2A>G Likely pathogenic ★★ same condition
MTTP c.2342+1G>A 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-arg540his (accessed [today's date]).

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