Is SETD1B p.Glu1237Lys (c.3709G>A) pathogenic?

SETD1B p.Glu1237Lys (c.3709G>A) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely benign (0.0768); Very rare (popmax 0.00196%, amr).

How common is SETD1B p.Glu1237Lys (c.3709G>A) in the general population?

SETD1B p.Glu1237Lys (c.3709G>A) is very rare (popmax 0.00196%, amr) (gnomAD).

What do computational predictors say about SETD1B p.Glu1237Lys (c.3709G>A)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

SETD1B p.Glu1237Lys

c.3709G>A · rs1024820256 · VCV3067396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.97	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 6.5	GERP 0.35, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	16.06	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 0.00196% Admixed American · 1/50,986 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000709% 11/1,551,028 alleles · very rare exomes 9/1,398,852 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	50,986
Remaining individualsnot grpmax-eligible	0.00166%	60,062
African / African-American	0.00137%	73,018
South Asian	0.00119%	84,048
European (non-Finnish)	0.00061%	163,856

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.Glu1237Lys
Coding: c.3709G>A
MANE Select: NM_001353345
dbSNP: rs1024820256
Type: single nucleotide variant
Location: chr12:121819694 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1237: a UniProt-annotated variant site (in iddseld); the 'disordered' region

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

Similar variants

SETD1B p.Arg1329Ter Pathogenic ★★ same type
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SETD1B p.Arg1825Trp Likely pathogenic ★★ same type
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Gln780Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Glu1948Lys Pathogenic/Likely pathogenic ★★ 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/setd1b-p-glu1237lys (accessed [today's date]).

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