Is MTOR p.Ala204= (c.612C>T) pathogenic?

MTOR p.Ala204= (c.612C>T) is classified Uncertain significance in MTOR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-26). Very rare (popmax 0.000339%, nfe); Associated with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome.

How common is MTOR p.Ala204= (c.612C>T) in the general population?

MTOR p.Ala204= (c.612C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

MTOR p.Ala204=

Q: What condition is associated with MTOR p.Ala204= (c.612C>T)?

MTOR p.Ala204= (c.612C>T) is associated with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ClinVar).

c.612C>T · VCV4974630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -0.64, phastCons 1
Overall
CADD	9.686	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,044 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,132 alleles · very rare exomes 4/1,461,874 · genomes 0/152,258 · joint denominator

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.Ala204=
Coding: c.612C>T
MANE Select: NM_004958
Type: single nucleotide variant
Location: chr1:11256085 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 204: an α-helix; the 'interaction with nbn' region

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.Ala204Pro Uncertain significance ★ same residue
MTOR p.Ala204Thr 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

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-ala204 (accessed [today's date]).

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