Is SETD1B p.Pro1340Ala (c.4018C>G) pathogenic?

SETD1B p.Pro1340Ala (c.4018C>G) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely benign (0.0722); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro1340Ala (c.4018C>G)?

SETD1B p.Pro1340Ala (c.4018C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro1340Ala (c.4018C>G) in the general population?

SETD1B p.Pro1340Ala (c.4018C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD1B p.Pro1340Ala (c.4018C>G)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

SETD1B p.Pro1340Ala

c.4018C>G · rs375852395 · VCV3160617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.29	benign-leaning
SaProt	LLR -7.04	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 3.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	20.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETD1B
Protein: p.Pro1340Ala
Coding: c.4018C>G
MANE Select: NM_001353345
dbSNP: rs375852395
Type: single nucleotide variant
Location: chr12:121822597 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1340: a UniProt-annotated variant site (in iddseld); the 'disordered' region

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1B p.Ala1657Val Uncertain significance ★★ ⚠ same condition
SETD1B p.Ala654Thr Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1428Trp Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1458His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1643His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1670Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg467Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Asp1107Asn Uncertain significance ★★ ⚠ same condition

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/setd1b-p-pro1340ala (accessed [today's date]).

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