Is MTOR p.Leu599Pro (c.1796T>C) pathogenic?

MTOR p.Leu599Pro (c.1796T>C) is classified Conflicting classifications of pathogenicity in MTOR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.9915); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with MTOR p.Leu599Pro (c.1796T>C)?

MTOR p.Leu599Pro (c.1796T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MTOR p.Leu599Pro (c.1796T>C) in the general population?

MTOR p.Leu599Pro (c.1796T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MTOR p.Leu599Pro (c.1796T>C)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

MTOR p.Leu599Pro

c.1796T>C · rs769668717 · VCV697789

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 18 kb · p 7.9e-08 · regional, not allelic
Overall
CADD	27.4	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 0.00134% African / African-American · 1/74,902 alleles

Filtering AF 0.00069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.000993% 16/1,610,914 alleles · very rare exomes 11/1,458,660 · genomes 5/152,254 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,354
African / African-Americangrpmax	0.00134%	74,902
European (non-Finnish)	0.00119%	84,109

Remaining individuals 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: MTOR
Protein: p.Leu599Pro
Coding: c.1796T>C
MANE Select: NM_004958
dbSNP: rs769668717
Type: single nucleotide variant
Location: chr1:11238608 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 599: the 'interaction with nbn' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTOR p.Leu599= Likely benign ★ same residue
MTOR c.5365-5A>G Uncertain significance ★★ same condition
MTOR p.Ala352Ser Uncertain significance ★★ ⚠ same condition
MTOR p.Arg1818Cys Uncertain significance ★★ ⚠ same condition
MTOR p.Arg2060Gln Uncertain significance ★★ ⚠ same condition
MTOR p.Arg2110Gln Uncertain significance ★★ ⚠ same condition
MTOR p.Arg2217Gln Uncertain significance ★★ ⚠ same condition
MTOR p.Arg2445Gly Uncertain significance ★★ 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/mtor-p-leu599pro (accessed [today's date]).

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