Is MTOR p.Val520Ala (c.1559T>C) pathogenic?

MTOR p.Val520Ala (c.1559T>C) is classified Uncertain significance in MTOR (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-21). AlphaMissense: ambiguous (0.4124); Very rare (popmax 8.47e-05%, nfe); Associated with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome.

How common is MTOR p.Val520Ala (c.1559T>C) in the general population?

MTOR p.Val520Ala (c.1559T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MTOR p.Val520Ala (c.1559T>C)?

AlphaMissense predicts ambiguous (score 0.4124) — an in-silico prediction, not a clinical call.

MTOR p.Val520Ala

Q: What condition is associated with MTOR p.Val520Ala (c.1559T>C)?

MTOR p.Val520Ala (c.1559T>C) is associated with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ClinVar).

c.1559T>C · rs2523333227 · VCV2433827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Computational evidence

Protein change
AlphaMissense	0.4124	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -6.82	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	21.4	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 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.2e-05% 1/1,614,176 alleles · very rare exomes 1/1,461,848 · genomes 0/152,328 · 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.Val520Ala
Coding: c.1559T>C
MANE Select: NM_004958
dbSNP: rs2523333227
Type: single nucleotide variant
Location: chr1:11240530 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 520: 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.Val520= Likely benign ★ 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-val520ala (accessed [today's date]).

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