Is DISC1 p.Leu330= (c.990C>T) pathogenic?

DISC1 p.Leu330= (c.990C>T) is classified Likely benign in DISC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-12). Very rare (popmax 0.000678%, nfe).

How common is DISC1 p.Leu330= (c.990C>T) in the general population?

DISC1 p.Leu330= (c.990C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

DISC1 p.Leu330=

c.990C>T · rs557511436 · VCV750973

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.4
Overall
CADD	1.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,060 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00291% 47/1,613,994 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.125%	800
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)grpmax	0.000678%	147,507

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu330=
Coding: c.990C>T
MANE Select: NM_018662
dbSNP: rs557511436
Type: single nucleotide variant
Location: chr1:231694748 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 330: a UniProt-annotated variant site (in); the 'interaction with traf3ip1' region

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

Similar variants

DISC1 p.Leu330Phe Benign ★★ ⚠ same residue
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.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-leu330 (accessed [today's date]).

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