Is DISC1 p.Glu751Gln (c.2251G>C) pathogenic?

DISC1 p.Glu751Gln (c.2251G>C) is classified Benign in DISC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.113); Low-frequency (popmax 1.55%, nfe).

How common is DISC1 p.Glu751Gln (c.2251G>C) in the general population?

DISC1 p.Glu751Gln (c.2251G>C) is low-frequency (popmax 1.55%, nfe) (gnomAD).

What do computational predictors say about DISC1 p.Glu751Gln (c.2251G>C)?

AlphaMissense predicts likely benign (score 0.113) — an in-silico prediction, not a clinical call.

DISC1 p.Glu751Gln

c.2251G>C · rs115112816 · VCV773422

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.113 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.55%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.113	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Pangolin	Δ0.27	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 0.66, phastCons 0.97
Regional constraint	o/e 1.05	unconstrained · MANE · 266 kb · p 0.32 · regional, not allelic
Overall
CADD	18.51	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 1.55% European (non-Finnish) · 18,322/1,179,848 alleles

Filtering AF 1.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 1.34% 21,609/1,613,892 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.62%	28
Amishnot grpmax-eligible	2.63%	38
European (non-Finnish)grpmax	1.55%	64
Remaining individualsnot grpmax-eligible	1.23%	81
Middle Eastern	0.875%	114
Finnishnot grpmax-eligible	0.828%	121
Admixed American	0.522%	192
South Asian	0.379%	264
African / African-American	0.243%	412

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.Glu751Gln
Coding: c.2251G>C
MANE Select: NM_018662
dbSNP: rs115112816
Type: single nucleotide variant
Location: chr1:232008993 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.74 · 1 PDB
Residue 751: the 'interaction with pafah1b1' region; the 'necessary and sufficient for interaction with pcnt and localization at the centrosome' region; the 'interaction with atf4 and atf5' region

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

Similar variants

DISC1 p.Glu751Ala Uncertain significance ★ ⚠ same residue
DISC1 p.Cys187Tyr Uncertain significance ★★ ⚠ same type
DISC1 p.Arg170Cys Benign ★★ same type
DISC1 p.Arg345Gln 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-glu751gln (accessed [today's date]).

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