Is MTTP p.Met84Thr (c.251T>C) pathogenic?

MTTP p.Met84Thr (c.251T>C) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.5196); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with MTTP p.Met84Thr (c.251T>C)?

MTTP p.Met84Thr (c.251T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MTTP p.Met84Thr (c.251T>C) in the general population?

MTTP p.Met84Thr (c.251T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MTTP p.Met84Thr (c.251T>C)?

AlphaMissense predicts ambiguous (score 0.5196) — an in-silico prediction, not a clinical call.

MTTP p.Met84Thr

c.251T>C · VCV4625323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5196	ambiguous
REVEL	0.145	moderately benign-leaning
SaProt	LLR -6.92	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	21.7	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 0.00133% African / African-American · 1/74,944 alleles

Overall 6.85e-05% 1/1,460,804 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.Met84Thr
Coding: c.251T>C
MANE Select: NM_001386140
Type: single nucleotide variant
Location: chr4:99583375 (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 84: the vitellogenin domain; a β-strand

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.Met84Leu 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-met84thr (accessed [today's date]).

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