Is MTOR p.Ser2215Phe (c.6644C>T) pathogenic?

MTOR p.Ser2215Phe (c.6644C>T) is classified Pathogenic in MTOR (ClinVar, Expert panel, 5 submitters; last evaluated 2022-02-12). AlphaMissense: likely pathogenic (0.9248); Absent from gnomAD v4.1; Associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

How common is MTOR p.Ser2215Phe (c.6644C>T) in the general population?

MTOR p.Ser2215Phe (c.6644C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTOR p.Ser2215Phe (c.6644C>T)?

AlphaMissense predicts likely pathogenic (score 0.9248) — an in-silico prediction, not a clinical call.

MTOR p.Ser2215Phe

Q: What condition is associated with MTOR p.Ser2215Phe (c.6644C>T)?

MTOR p.Ser2215Phe (c.6644C>T) is associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, isolated focal cortical dysplasia type II (ClinVar).

c.6644C>T · rs587777894 · VCV156703

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9248 · 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

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

PM2_Supporting PS3_Supporting PS2_Strong PS4 PP2

Curation rationale (ClinGen, verbatim)

The c.6644C>T (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Ser2215Phe). This variant is absent from gnomAD v2.1.1 (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 has been shown to significantly increase phosphorylation levels in experiments with case and control cells of similar isogenic backgrounds indicating that this variant impacts protein function (PMID: 27159400) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs: 27159400, 27830187 ; identified in 8 individuals with neuropathology confirmatory of a malformation of cortical development and 19 tumor samples in the literature and COSMIC). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMIDs: 27159400, 27159400, 27830187). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic 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_P, PP2, PS3_P, PS4, PS2; 11 points (VCEP specifications version 1; Approved: 1/31/2021)

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

Computational evidence

Protein change
AlphaMissense	0.9248	likely pathogenic ✓ concordant with ClinVar
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 14 kb · p 6.9e-46 · regional, not allelic
Overall
CADD	28.6	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.Ser2215Phe
Coding: c.6644C>T
MANE Select: NM_004958
dbSNP: rs587777894
Type: single nucleotide variant
Location: chr1:11124516 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 2215: a UniProt-annotated variant site (in fcord2; somatic mutation; increased tor signaling); a UniProt-annotated variant site (in fcord2; also found in a colorectal adenocarcinoma sample; somatic mutation; increased tor signaling); an α-helix; the pi3k/pi4k catalytic 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: isolated focal cortical dysplasia type II

Similar variants

MTOR p.Ser2215Tyr Pathogenic ★★★ same residue
MTOR p.Ser2215Pro Likely pathogenic ★ same residue
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.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-ser2215phe (accessed [today's date]).

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