Is DISC1 p.Ala659= (c.1977C>T) pathogenic?

DISC1 p.Ala659= (c.1977C>T) is classified Likely benign in DISC1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-12-09). Very rare (popmax 0.000763%, nfe); Associated with DISC1-related disorder.

What condition is associated with DISC1 p.Ala659= (c.1977C>T)?

DISC1 p.Ala659= (c.1977C>T) is associated with DISC1-related disorder (ClinVar).

How common is DISC1 p.Ala659= (c.1977C>T) in the general population?

DISC1 p.Ala659= (c.1977C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

DISC1 p.Ala659=

c.1977C>T · rs781439697 · VCV3031196

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

DISC1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.034	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -3.9
Overall
CADD	5.493	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,952 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,010 alleles · very rare exomes 9/1,461,742 · genomes 0/152,268 · 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: DISC1
Protein: p.Ala659=
Coding: c.1977C>T
MANE Select: NM_018662
dbSNP: rs781439697
Type: single nucleotide variant
Location: chr1:231818513 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 659: the 'interaction with traf3ip1' region; the 'necessary and sufficient for interaction with pcnt and localization at the centrosome' region; the 'interaction with atf4 and atf5' region

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

Disease context

DISC1-related disorder

Similar variants

DISC1 p.Ala659Val Uncertain significance ★ ⚠ same residue
DISC1 p.Cys187Tyr Uncertain significance ★★ ⚠ same condition
DISC1 p.Arg454Ile 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

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-ala659 (accessed [today's date]).

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