Is MTTP p.Val42Ile (c.124G>A) pathogenic?

MTTP p.Val42Ile (c.124G>A) is classified Conflicting classifications of pathogenicity in MTTP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.095); Rare (popmax 0.339%, eas); Associated with abetalipoproteinemia.

What condition is associated with MTTP p.Val42Ile (c.124G>A)?

MTTP p.Val42Ile (c.124G>A) is associated with abetalipoproteinemia (ClinVar).

How common is MTTP p.Val42Ile (c.124G>A) in the general population?

MTTP p.Val42Ile (c.124G>A) is rare (popmax 0.339%, eas) (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.Val42Ile (c.124G>A)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

MTTP p.Val42Ile

c.124G>A · rs756998920 · VCV716451

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.339%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

abetalipoproteinemia

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	24.2	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 0.339% East Asian · 152/44,878 alleles

Filtering AF 0.295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.278%

Overall 0.011% 177/1,614,182 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.339%	295
Remaining individualsnot grpmax-eligible	0.0224%	4,465
South Asian	0.00549%	18,218
European (non-Finnish)	0.000508%	196,670

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.Val42Ile
Coding: c.124G>A
MANE Select: NM_001386140
dbSNP: rs756998920
Type: single nucleotide variant
Location: chr4:99581967 (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 42: 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.Val42= Likely benign ★ 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
MTTP c.502-1G>C 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-val42ile (accessed [today's date]).

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