Is MRTO4 p.Leu26Val (c.76C>G) pathogenic?

MRTO4 p.Leu26Val (c.76C>G) is classified Uncertain significance in MRTO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: ambiguous (0.3957); Absent from gnomAD v4.1.

How common is MRTO4 p.Leu26Val (c.76C>G) in the general population?

MRTO4 p.Leu26Val (c.76C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MRTO4 p.Leu26Val (c.76C>G)?

AlphaMissense predicts ambiguous (score 0.3957) — an in-silico prediction, not a clinical call.

MRTO4 p.Leu26Val

c.76C>G · VCV3874803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3957	ambiguous
REVEL	0.266	benign-leaning
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,991 bp · p 0.83 · regional, not allelic
Overall
CADD	22.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MRTO4
Protein: p.Leu26Val
Coding: c.76C>G
MANE Select: NM_016183
Type: single nucleotide variant
Location: chr1:19254829 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 89.84 · 35 PDB
Residue 26: an α-helix

Full MRTO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MRTO4 c.493+2T>A Uncertain significance ★ same type
MRTO4 p.Ala59Thr Uncertain significance ★ ⚠ same type
MRTO4 p.Arg107Ser Uncertain significance ★ ⚠ same type
MRTO4 p.Arg126Leu Uncertain significance ★ ⚠ same type
MRTO4 p.Arg126Pro Uncertain significance ★ ⚠ same type
MRTO4 p.Arg188His Uncertain significance ★ ⚠ same type
MRTO4 p.Arg214Ser Uncertain significance ★ ⚠ same type
MRTO4 p.Arg57Gln Uncertain significance ★ ⚠ 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/mrto4-p-leu26val (accessed [today's date]).

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