Is DISC1 p.Val18Met (c.52G>A) pathogenic?

DISC1 p.Val18Met (c.52G>A) is classified Uncertain significance in DISC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.3031); Very rare (popmax 0.000705%, nfe).

How common is DISC1 p.Val18Met (c.52G>A) in the general population?

DISC1 p.Val18Met (c.52G>A) is very rare (popmax 0.000705%, nfe) (gnomAD).

What do computational predictors say about DISC1 p.Val18Met (c.52G>A)?

AlphaMissense predicts likely benign (score 0.3031) — an in-silico prediction, not a clinical call.

DISC1 p.Val18Met

c.52G>A · VCV3840185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000705%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3031	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -0.95
Regional constraint	o/e 1.04	unconstrained · MANE · 68 kb · p 0.48 · regional, not allelic
Overall
CADD	16.59	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 0.000705% European (non-Finnish) · 8/1,134,660 alleles

Filtering AF 0.000303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000532% 8/1,504,910 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.Val18Met
Coding: c.52G>A
MANE Select: NM_018662
Type: single nucleotide variant
Location: chr1:231626919 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 18: the 'interaction with map1a' region; the 'disordered' 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-val18met (accessed [today's date]).

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