Is SETD1B p.Arg1748Ser (c.5242C>A) pathogenic?

SETD1B p.Arg1748Ser (c.5242C>A) is classified Pathogenic in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with seizures and language delay.

What condition is associated with SETD1B p.Arg1748Ser (c.5242C>A)?

SETD1B p.Arg1748Ser (c.5242C>A) is associated with intellectual developmental disorder with seizures and language delay (ClinVar).

How common is SETD1B p.Arg1748Ser (c.5242C>A) in the general population?

SETD1B p.Arg1748Ser (c.5242C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD1B p.Arg1748Ser (c.5242C>A)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

SETD1B p.Arg1748Ser

c.5242C>A · VCV4526184

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with seizures and language delay

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 3% in SETD1B
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -14.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 3,914 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	24.6	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

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.Arg1748Ser
Coding: c.5242C>A
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121825271 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1748: a UniProt-annotated variant site (in iddseld); an α-helix

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

Disease context

intellectual developmental disorder with seizures and language delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same residue
SETD1B p.Arg1748His Pathogenic ★ same residue
SETD1B p.Arg1329Ter Pathogenic ★★ same condition
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETD1B p.Arg1825Trp Likely pathogenic ★★ same condition
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Gln780Ter Pathogenic/Likely pathogenic ★★ 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-arg1748ser (accessed [today's date]).

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