Is MTOR p.Arg1154= (c.3462G>T) pathogenic?

MTOR p.Arg1154= (c.3462G>T) is classified Conflicting classifications of pathogenicity in MTOR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-05). Very rare (popmax 0.000424%, nfe); Associated with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome.

How common is MTOR p.Arg1154= (c.3462G>T) in the general population?

MTOR p.Arg1154= (c.3462G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

MTOR p.Arg1154=

Q: What condition is associated with MTOR p.Arg1154= (c.3462G>T)?

MTOR p.Arg1154= (c.3462G>T) is associated with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ClinVar).

c.3462G>T · rs17036536 · VCV3237443

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -2.7	GERP -4.2
Overall
CADD	12.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,030 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)grpmax	0.000424%	236,006

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.Arg1154=
Coding: c.3462G>T
MANE Select: NM_004958
dbSNP: rs17036536
Type: single nucleotide variant
Location: chr1:11212411 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 1154: an α-helix

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

Disease context

macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTOR p.Arg1154Gln Uncertain significance ★★ ⚠ same residue
MTOR p.Cys1483Tyr Pathogenic ★★★ same condition
MTOR p.Thr1977Lys Pathogenic ★★★ same condition
MTOR p.Trp1490Arg Likely pathogenic ★★★ same condition
MTOR p.Glu1799Lys Pathogenic ★★ ⚠ same condition
MTOR p.Glu2419Lys Pathogenic ★★ same condition
MTOR p.Met2327Ile Pathogenic ★★ same condition
MTOR p.Phe1888Cys Pathogenic/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/mtor-p-arg1154 (accessed [today's date]).

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