Is DISC1 p.Ile596Thr (c.1787T>C) pathogenic?

DISC1 p.Ile596Thr (c.1787T>C) is classified Uncertain significance in DISC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely pathogenic (0.8139); Absent from gnomAD v4.1.

How common is DISC1 p.Ile596Thr (c.1787T>C) in the general population?

DISC1 p.Ile596Thr (c.1787T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DISC1 p.Ile596Thr (c.1787T>C)?

AlphaMissense predicts likely pathogenic (score 0.8139) — an in-silico prediction, not a clinical call.

DISC1 p.Ile596Thr

c.1787T>C · VCV3502147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8139 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8139	likely pathogenic · top 3% in DISC1
REVEL	0.062	moderately benign-leaning
SaProt	LLR -9.37	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 2.4	GERP 0.49, phastCons 0.1
Regional constraint	o/e 1.05	unconstrained · MANE · 266 kb · p 0.32 · regional, not allelic
Overall
CADD	21.0	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.Ile596Thr
Coding: c.1787T>C
MANE Select: NM_018662
Type: single nucleotide variant
Location: chr1:231800205 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 596: 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

Similar variants

DISC1 p.Cys187Tyr Uncertain significance ★★ ⚠ same type
DISC1 p.Arg170Cys Benign ★★ same type
DISC1 p.Arg345Gln Benign ★★ same type
DISC1 p.Glu751Gln Benign ★★ same type
DISC1 p.Leu330Phe Benign ★★ ⚠ same type
DISC1 p.Pro432Leu Likely benign ★★ same type
DISC1 p.Ala13Thr Uncertain significance ★ ⚠ same type
DISC1 p.Ala220Val 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/disc1-p-ile596thr (accessed [today's date]).

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