Is MTTP p.Gly151Ser (c.451G>A) pathogenic?

MTTP p.Gly151Ser (c.451G>A) is classified Uncertain significance in MTTP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.5163); Ultra-rare (popmax 0.0496%, mid); Associated with abetalipoproteinemia.

What condition is associated with MTTP p.Gly151Ser (c.451G>A)?

MTTP p.Gly151Ser (c.451G>A) is associated with abetalipoproteinemia (ClinVar).

How common is MTTP p.Gly151Ser (c.451G>A) in the general population?

MTTP p.Gly151Ser (c.451G>A) is ultra-rare (popmax 0.0496%, 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.Gly151Ser (c.451G>A)?

AlphaMissense predicts ambiguous (score 0.5163) — an in-silico prediction, not a clinical call.

MTTP p.Gly151Ser

c.451G>A · rs867316992 · VCV1209606

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5163 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

abetalipoproteinemia

Computational evidence

Protein change
AlphaMissense	0.5163	ambiguous
REVEL	0.66	pathogenic-leaning
SaProt	LLR -8.14	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	26.2	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 0.0496% Middle Eastern · 3/6,054 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.000248% 4/1,610,372 alleles · ultra-rare exomes 4/1,458,122 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,018
Remaining individualsnot grpmax-eligible	0.0016%	62,378

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.Gly151Ser
Coding: c.451G>A
MANE Select: NM_001386140
dbSNP: rs867316992
Type: single nucleotide variant
Location: chr4:99589700 (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 151: 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.Gly151= Benign ★★ same residue
MTTP p.Gly151Val Uncertain significance ★ ⚠ 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

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-gly151ser (accessed [today's date]).

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