Is MTTP p.Ser252= (c.756G>A) pathogenic?

MTTP p.Ser252= (c.756G>A) is classified Conflicting classifications of pathogenicity in MTTP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-24). Very rare (popmax 0.00771%, sas); Associated with abetalipoproteinemia.

What condition is associated with MTTP p.Ser252= (c.756G>A)?

MTTP p.Ser252= (c.756G>A) is associated with abetalipoproteinemia (ClinVar).

How common is MTTP p.Ser252= (c.756G>A) in the general population?

MTTP p.Ser252= (c.756G>A) is very rare (popmax 0.00771%, sas) (gnomAD).

How is Abetalipoproteinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MTTP p.Ser252=

c.756G>A · rs750749323 · VCV900056

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00771%, sas)

Conditions

abetalipoproteinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.4	GERP -2.5
Overall
CADD	2.848	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00771% South Asian · 7/90,824 alleles

Filtering AF 0.0036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00149% 24/1,610,458 alleles · very rare exomes 23/1,458,414 · genomes 1/152,044 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00771%	12,975
Admixed American	0.00334%	29,929
African / African-American	0.00134%	74,794
European (non-Finnish)	0.00119%	84,100

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.Ser252=
Coding: c.756G>A
MANE Select: NM_001386140
dbSNP: rs750749323
Type: single nucleotide variant
Location: chr4:99591788 (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 252: the vitellogenin domain; a β-strand

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.Ser252Ter Likely pathogenic ★ same residue
MTTP p.Ser252Leu 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-ser252 (accessed [today's date]).

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