Is MTOR p.Trp1490Arg (c.4468T>C) pathogenic?

MTOR p.Trp1490Arg (c.4468T>C) is classified Likely pathogenic in MTOR (ClinVar, Expert panel, 2 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1; Associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

What condition is associated with MTOR p.Trp1490Arg (c.4468T>C)?

MTOR p.Trp1490Arg (c.4468T>C) is associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ClinVar).

How common is MTOR p.Trp1490Arg (c.4468T>C) in the general population?

MTOR p.Trp1490Arg (c.4468T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTOR p.Trp1490Arg (c.4468T>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

MTOR p.Trp1490Arg

c.4468T>C · rs2100566800 · VCV1296993

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

ClinGen expert panel — Brain Malformations VCEP

Likely Pathogenic for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes. Applied ACMG criteria (verbatim):

PM2_Supporting PS2_Moderate PM1_Supporting PS4_Moderate PP2

Curation rationale (ClinGen, verbatim)

The NM_004958.4:c.4468T>C variant in MTOR is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 1490 (p.Trp1490Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BM VCEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). This variant has been identified as a de novo occurrence with parental relationships confirmed in one individual with macrocephaly ( >=2 SD) and developmental delay or intellectual disability without cortical malformations (PS2_M, PS4_M; PMID: 27830187). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_supporting, PP2, PM1_supporting, PS4_moderate, PS2_moderate; 7 points (VCEP specifications version 1.1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic ✓ concordant with ClinVar · top 5% in MTOR
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -13.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 27 kb · p 1.1e-17 · regional, not allelic
Overall
CADD	31.0	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: MTOR
Protein: p.Trp1490Arg
Coding: c.4468T>C
MANE Select: NM_004958
dbSNP: rs2100566800
Type: single nucleotide variant
Location: chr1:11157153 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 1490: a UniProt-annotated variant site (in sks); an α-helix; the fat domain

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

Disease context

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Similar variants

MTOR p.Ala1669Ser Likely pathogenic ★★★ ⚠ same condition
MTOR p.Cys1483Arg Pathogenic ★★★ same condition
MTOR p.Cys1483Tyr Pathogenic ★★★ same condition
MTOR p.Leu1460Pro Pathogenic ★★★ same condition
MTOR p.Leu2427Pro Pathogenic ★★★ same condition
MTOR p.Ser2215Phe Pathogenic ★★★ same condition
MTOR p.Ser2215Tyr Pathogenic ★★★ same condition
MTOR p.Thr1977Arg 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-trp1490arg (accessed [today's date]).

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