Is MTTP p.Leu79Val (c.235T>G) pathogenic?

MTTP p.Leu79Val (c.235T>G) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-17). AlphaMissense: likely benign (0.1502); Very rare (popmax 0.00167%, amr).

How common is MTTP p.Leu79Val (c.235T>G) in the general population?

MTTP p.Leu79Val (c.235T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MTTP p.Leu79Val (c.235T>G)?

AlphaMissense predicts likely benign (score 0.1502) — an in-silico prediction, not a clinical call.

MTTP p.Leu79Val

c.235T>G · rs1210122454 · VCV2187945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1502	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.98	donor gain · deltas
Pangolin	Δ0.67	gain · loss 0.40 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.8	GERP 0.78, phastCons 0.23
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,018 alleles

Overall 0.000124% 2/1,614,160 alleles · very rare exomes 2/1,461,830 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Admixed Americangrpmax	0.00167%	60,018

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu79Val
Coding: c.235T>G
MANE Select: NM_001386140
dbSNP: rs1210122454
Type: single nucleotide variant
Location: chr4:99582078 (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 79: the vitellogenin domain; a β-strand

Full MTTP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTTP p.Leu79Trp Uncertain significance ★ ⚠ same residue
MTTP p.Leu79fs Likely pathogenic ★ same residue
MTTP c.1067+1G>C Likely pathogenic ★★ same type
MTTP c.1236+1G>A Pathogenic/Likely pathogenic ★★ same type
MTTP c.1769+2T>C Pathogenic/Likely pathogenic ★★ same type
MTTP c.1867+1G>A Pathogenic ★★ same type
MTTP c.1867+5G>A Pathogenic/Likely pathogenic ★★ same type
MTTP c.1868-2A>G Likely pathogenic ★★ same type

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-leu79val (accessed [today's date]).

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