Is SETD1B p.Ser1063= (c.3189G>A) pathogenic?

SETD1B p.Ser1063= (c.3189G>A) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-11). Very rare (popmax 0.00119%, sas); Associated with SETD1B-related disorder.

What condition is associated with SETD1B p.Ser1063= (c.3189G>A)?

SETD1B p.Ser1063= (c.3189G>A) is associated with SETD1B-related disorder (ClinVar).

How common is SETD1B p.Ser1063= (c.3189G>A) in the general population?

SETD1B p.Ser1063= (c.3189G>A) is very rare (popmax 0.00119%, sas) (gnomAD).

SETD1B p.Ser1063=

c.3189G>A · rs1414424089 · VCV2633095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Conditions

SETD1B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.74	acceptor gain · deltas
Pangolin	Δ0.25	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -11	GERP -2.6
Overall
CADD	16.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% South Asian · 1/84,060 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000193% 3/1,551,210 alleles · very rare exomes 2/1,399,050 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00119%	84,060
European (non-Finnish)	0.000174%	573,362

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.Ser1063=
Coding: c.3189G>A
MANE Select: NM_001353345
dbSNP: rs1414424089
Type: single nucleotide variant
Location: chr12:121817581 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1063: 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

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-ser1063 (accessed [today's date]).

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