Is DISC1 p.Lys577Glu (c.1729A>G) pathogenic?

DISC1 p.Lys577Glu (c.1729A>G) is classified Uncertain significance in DISC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1558); Ultra-rare (popmax 0.0283%, nfe).

How common is DISC1 p.Lys577Glu (c.1729A>G) in the general population?

DISC1 p.Lys577Glu (c.1729A>G) is ultra-rare (popmax 0.0283%, nfe) (gnomAD).

What do computational predictors say about DISC1 p.Lys577Glu (c.1729A>G)?

AlphaMissense predicts likely benign (score 0.1558) — an in-silico prediction, not a clinical call.

DISC1 p.Lys577Glu

c.1729A>G · rs367543093 · VCV98354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1558	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP -0.66, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 266 kb · p 0.32 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% European (non-Finnish) · 334/1,179,710 alleles

Filtering AF 0.0258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.0218% 352/1,611,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0283%	3,532
Remaining individualsnot grpmax-eligible	0.0176%	5,675
Admixed American	0.00836%	11,966
African / African-American	0.00268%	37,333

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.Lys577Glu
Coding: c.1729A>G
MANE Select: NM_018662
dbSNP: rs367543093
Type: single nucleotide variant
Location: chr1:231800147 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 577: 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-lys577glu (accessed [today's date]).

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