Is MTTP p.Phe819Leu (c.2457T>G) pathogenic?

MTTP p.Phe819Leu (c.2457T>G) is classified Uncertain significance in MTTP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.9923); Ultra-rare (popmax 0.0283%, amr); Associated with Inborn genetic diseases.

What condition is associated with MTTP p.Phe819Leu (c.2457T>G)?

MTTP p.Phe819Leu (c.2457T>G) is associated with Inborn genetic diseases, abetalipoproteinemia (ClinVar).

How common is MTTP p.Phe819Leu (c.2457T>G) in the general population?

MTTP p.Phe819Leu (c.2457T>G) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about MTTP p.Phe819Leu (c.2457T>G)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

MTTP p.Phe819Leu

c.2457T>G · rs765341695 · VCV850026

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic · top 1% in MTTP
REVEL	0.589	indeterminate
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -3.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	21.8	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 0.0283% Admixed American · 17/59,992 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0013% 21/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,529
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000254%	393,323

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.Phe819Leu
Coding: c.2457T>G
MANE Select: NM_001386140
dbSNP: rs765341695
Type: single nucleotide variant
Location: chr4:99621175 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.73 · 2 PDB

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

Also linked: abetalipoproteinemia

Similar variants

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
MTTP c.502-2A>G 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-phe819leu (accessed [today's date]).

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