Is RICTOR p.Glu249Asp (c.747A>T) pathogenic?

RICTOR p.Glu249Asp (c.747A>T) is classified Uncertain significance in RICTOR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.3929); Very rare (popmax 0.0023%, nfe).

How common is RICTOR p.Glu249Asp (c.747A>T) in the general population?

RICTOR p.Glu249Asp (c.747A>T) is very rare (popmax 0.0023%, nfe) (gnomAD).

What do computational predictors say about RICTOR p.Glu249Asp (c.747A>T)?

AlphaMissense predicts ambiguous (score 0.3929) — an in-silico prediction, not a clinical call.

RICTOR p.Glu249Asp

c.747A>T · VCV4154228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3929	ambiguous
REVEL	0.241	benign-leaning
SaProt	LLR -5.21	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP -5.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 54 kb · p 8e-12 · regional, not allelic
Overall
CADD	16.56	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 0.0023% European (non-Finnish) · 27/1,174,274 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00168% 27/1,606,132 alleles · very rare exomes 27/1,453,842 · genomes 0/152,290 · 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: RICTOR
Protein: p.Glu249Asp
Coding: c.747A>T
MANE Select: NM_152756
Type: single nucleotide variant
Location: chr5:38981873 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 16 PDB
Residue 249: the 'interaction with nbn' region; a β-strand

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

Similar variants

RICTOR p.Asn749= Benign ★★ same type
RICTOR p.Ile811= Benign ★★ same type
RICTOR p.His442Arg Likely pathogenic ★ ⚠ same type
RICTOR p.Ala1350Thr Uncertain significance ★ ⚠ same type
RICTOR p.Ala146Thr Uncertain significance ★ ⚠ same type
RICTOR p.Ala246Val Uncertain significance ★ ⚠ same type
RICTOR p.Ala472Thr Uncertain significance ★ ⚠ same type
RICTOR p.Ala91Thr Uncertain significance ★ ⚠ same type

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/rictor-p-glu249asp (accessed [today's date]).

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