Is DISC1 p.Arg454Ile (c.1361G>T) pathogenic?

DISC1 p.Arg454Ile (c.1361G>T) is classified Uncertain significance in DISC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). AlphaMissense: likely pathogenic (0.6572); Absent from gnomAD v4.1; Associated with DISC1-related disorder.

What condition is associated with DISC1 p.Arg454Ile (c.1361G>T)?

DISC1 p.Arg454Ile (c.1361G>T) is associated with DISC1-related disorder (ClinVar).

How common is DISC1 p.Arg454Ile (c.1361G>T) in the general population?

DISC1 p.Arg454Ile (c.1361G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DISC1 p.Arg454Ile (c.1361G>T)?

AlphaMissense predicts likely pathogenic (score 0.6572) — an in-silico prediction, not a clinical call.

DISC1 p.Arg454Ile

c.1361G>T · rs2546066166 · VCV2633720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6572 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DISC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.6572	likely pathogenic · top 6% in DISC1
REVEL	0.261	benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 77 kb · p 8.4e-06 · regional, not allelic
Overall
CADD	24.7	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: DISC1
Protein: p.Arg454Ile
Coding: c.1361G>T
MANE Select: NM_018662
dbSNP: rs2546066166
Type: single nucleotide variant
Location: chr1:231767232 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 454: the 'interaction with traf3ip1' region; the 'required for localization to punctate cytoplasmic foci' region; the 'necessary and sufficient for interaction with pcnt and localization at the centrosome' region

Full DISC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DISC1-related disorder

Similar variants

DISC1 p.Cys187Tyr Uncertain significance ★★ ⚠ same condition
DISC1 p.Ile773= Uncertain significance ★ same condition
DISC1 p.Pro231Ser Uncertain significance ★ ⚠ same condition
DISC1 p.Gln498Pro Uncertain significance ⚠ same condition
DISC1 c.1117+18828G>A Likely benign same condition
DISC1 c.1634+13T>G Likely benign same condition
DISC1 c.1981+48069C>G Benign same condition
DISC1 c.1982-9T>C Likely benign 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/disc1-p-arg454ile (accessed [today's date]).

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