Is MTTP p.Arg594His (c.1781G>A) pathogenic?

MTTP p.Arg594His (c.1781G>A) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). AlphaMissense: likely benign (0.0958); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with MTTP p.Arg594His (c.1781G>A)?

MTTP p.Arg594His (c.1781G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MTTP p.Arg594His (c.1781G>A) in the general population?

MTTP p.Arg594His (c.1781G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MTTP p.Arg594His (c.1781G>A)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

MTTP p.Arg594His

c.1781G>A · rs201863511 · VCV3218424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,850 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00105% 17/1,613,492 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,425
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.00329%	30,356
Admixed American	0.00167%	59,976
Remaining individualsnot grpmax-eligible	0.0016%	62,494
African / African-American	0.00134%	74,782
European (non-Finnish)	0.000678%	147,483

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.Arg594His
Coding: c.1781G>A
MANE Select: NM_001386140
dbSNP: rs201863511
Type: single nucleotide variant
Location: chr4:99611154 (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 594: the vitellogenin domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTTP p.Arg594Cys Uncertain significance ★★ ⚠ same residue
MTTP p.Ala144Asp Uncertain significance ★★ ⚠ same condition
MTTP p.Ala339Val Uncertain significance ★★ ⚠ same condition
MTTP p.Ala464Thr Uncertain significance ★★ ⚠ same condition
MTTP p.Ala493Ser Uncertain significance ★★ ⚠ same condition
MTTP p.Ala577Thr Uncertain significance ★★ ⚠ same condition
MTTP p.Ala883Asp Uncertain significance ★★ ⚠ same condition
MTTP p.Arg312Gly Uncertain significance ★★ ⚠ 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-arg594his (accessed [today's date]).

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