Is SETD1B p.Ser994= (c.2982C>T) pathogenic?

SETD1B p.Ser994= (c.2982C>T) is classified Likely benign in SETD1B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-12). Very rare (popmax 0.00138%, afr); Associated with SETD1B-related disorder.

What condition is associated with SETD1B p.Ser994= (c.2982C>T)?

SETD1B p.Ser994= (c.2982C>T) is associated with SETD1B-related disorder (ClinVar).

How common is SETD1B p.Ser994= (c.2982C>T) in the general population?

SETD1B p.Ser994= (c.2982C>T) is very rare (popmax 0.00138%, afr) (gnomAD).

SETD1B p.Ser994=

c.2982C>T · VCV3355184

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Conditions

SETD1B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -2.4
Overall
CADD	0.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00138% African / African-American · 1/72,594 alleles

Filtering AF 0.000191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000125%

Overall 0.000459% 7/1,524,296 alleles · very rare exomes 6/1,372,064 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00138%	72,594
European (non-Finnish)	0.000531%	188,433

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.Ser994=
Coding: c.2982C>T
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121817374 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 994: a modified residue (phosphoserine); 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.Ser994Tyr Uncertain significance ★ ⚠ same residue
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

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-ser994 (accessed [today's date]).

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