Is SETD1B p.Thr415= (c.1245C>T) pathogenic?

SETD1B p.Thr415= (c.1245C>T) is classified Likely benign in SETD1B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-08). Ultra-rare (popmax 0.0155%, sas); Associated with SETD1B-related disorder.

What condition is associated with SETD1B p.Thr415= (c.1245C>T)?

SETD1B p.Thr415= (c.1245C>T) is associated with SETD1B-related disorder (ClinVar).

How common is SETD1B p.Thr415= (c.1245C>T) in the general population?

SETD1B p.Thr415= (c.1245C>T) is ultra-rare (popmax 0.0155%, sas) (gnomAD).

SETD1B p.Thr415=

c.1245C>T · rs768205948 · VCV3058804

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, sas)

Conditions

SETD1B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.3	GERP -3.3
Overall
CADD	0.586	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0155% South Asian · 13/84,036 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00297% 46/1,549,600 alleles · ultra-rare exomes 45/1,397,468 · genomes 1/152,132 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0155%	6,464
East Asian	0.0122%	8,180
European (non-Finnish)	0.00235%	42,475
Remaining individualsnot grpmax-eligible	0.00166%	60,062

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.Thr415=
Coding: c.1245C>T
MANE Select: NM_001353345
dbSNP: rs768205948
Type: single nucleotide variant
Location: chr12:121810190 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 415: the 'disordered' region

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

Disease context

SETD1B-related disorder

Similar variants

SETD1B p.Tyr1943Cys Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Phe546Leu Uncertain significance ★★ ⚠ same condition
SETD1B c.544+1G>A Likely pathogenic ★ same condition
SETD1B p.Asp1893Asn Likely pathogenic ★ same condition
SETD1B p.Asp1893His Likely pathogenic ★ same condition
SETD1B p.Ala1003Val Uncertain significance ★ ⚠ same condition
SETD1B p.Ala1636Pro Uncertain significance ★ ⚠ same condition
SETD1B p.Ala431Val 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-thr415 (accessed [today's date]).

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