Is SETD1B p.Arg30Lys (c.89G>A) pathogenic?

SETD1B p.Arg30Lys (c.89G>A) is classified Uncertain significance in SETD1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-05). AlphaMissense: ambiguous (0.5119); Ultra-rare (popmax 0.0131%, sas); Associated with intellectual developmental disorder with seizures and language delay.

What condition is associated with SETD1B p.Arg30Lys (c.89G>A)?

SETD1B p.Arg30Lys (c.89G>A) is associated with intellectual developmental disorder with seizures and language delay (ClinVar).

How common is SETD1B p.Arg30Lys (c.89G>A) in the general population?

SETD1B p.Arg30Lys (c.89G>A) is ultra-rare (popmax 0.0131%, sas) (gnomAD).

What do computational predictors say about SETD1B p.Arg30Lys (c.89G>A)?

AlphaMissense predicts ambiguous (score 0.5119) — an in-silico prediction, not a clinical call.

SETD1B p.Arg30Lys

c.89G>A · rs752819288 · VCV1727208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, sas)

Conditions

intellectual developmental disorder with seizures and language delay

Computational evidence

Protein change
AlphaMissense	0.5119	ambiguous
REVEL	0.328	indeterminate
SaProt	LLR -7.21	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 4,864 bp · p 3.6e-21 · regional, not allelic
Overall
CADD	26.9	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 0.0131% South Asian · 11/84,014 alleles

Filtering AF 0.0073% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00561%

Overall 0.000838% 13/1,550,872 alleles · ultra-rare exomes 12/1,398,988 · genomes 1/151,884 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0131%	7,638
East Asian	0.00245%	40,824
European (non-Finnish)	8.72e-05%	1,146,818

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: SETD1B
Protein: p.Arg30Lys
Coding: c.89G>A
MANE Select: NM_001353345
dbSNP: rs752819288
Type: single nucleotide variant
Location: chr12:121804826 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB

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.Arg1329Ter Pathogenic ★★ same condition
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Arg1748Cys 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
SETD1B p.Glu1948Lys 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-arg30lys (accessed [today's date]).

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