Is DISC1 p.Pro540Arg (c.1619C>G) pathogenic?

DISC1 p.Pro540Arg (c.1619C>G) is classified Uncertain significance in DISC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.3049); Very rare (popmax 0.00562%, nfe).

How common is DISC1 p.Pro540Arg (c.1619C>G) in the general population?

DISC1 p.Pro540Arg (c.1619C>G) is very rare (popmax 0.00562%, nfe) (gnomAD).

What do computational predictors say about DISC1 p.Pro540Arg (c.1619C>G)?

AlphaMissense predicts likely benign (score 0.3049) — an in-silico prediction, not a clinical call.

DISC1 p.Pro540Arg

c.1619C>G · rs143165003 · VCV2463768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3049 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00562%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3049	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -12.62	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.1, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00562% European (non-Finnish) · 66/1,173,900 alleles

Filtering AF 0.00453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00413%

Overall 0.00431% 69/1,602,730 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00562%	17,786
Remaining individualsnot grpmax-eligible	0.00322%	31,024
Admixed American	0.00171%	58,338

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.Pro540Arg
Coding: c.1619C>G
MANE Select: NM_018662
dbSNP: rs143165003
Type: single nucleotide variant
Location: chr1:231771055 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 540: 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-pro540arg (accessed [today's date]).

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