Is DISC1 p.Phe535Leu (c.1605C>G) pathogenic?

DISC1 p.Phe535Leu (c.1605C>G) is classified Likely benign in DISC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.6674); Very rare (popmax 0.00169%, amr).

How common is DISC1 p.Phe535Leu (c.1605C>G) in the general population?

DISC1 p.Phe535Leu (c.1605C>G) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about DISC1 p.Phe535Leu (c.1605C>G)?

AlphaMissense predicts likely pathogenic (score 0.6674) — an in-silico prediction, not a clinical call.

DISC1 p.Phe535Leu

c.1605C>G · VCV4240799

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6674	likely pathogenic · top 6% in DISC1
REVEL	0.049	moderately benign-leaning
SaProt	LLR -4.63	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
Regional constraint	o/e 1.05	unconstrained · MANE · 266 kb · p 0.32 · regional, not allelic
Overall
CADD	7.83	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 0.00169% Admixed American · 1/59,068 alleles

Overall 6.87e-05% 1/1,455,434 alleles · very rare

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.Phe535Leu
Coding: c.1605C>G
MANE Select: NM_018662
Type: single nucleotide variant
Location: chr1:231771041 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 535: 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-phe535leu (accessed [today's date]).

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