Is SETD1A p.Ser963= (c.2889C>T) pathogenic?

SETD1A p.Ser963= (c.2889C>T) is classified Benign in SETD1A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-12). Common (popmax 14.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with SETD1A-related disorder.

What condition is associated with SETD1A p.Ser963= (c.2889C>T)?

SETD1A p.Ser963= (c.2889C>T) is associated with SETD1A-related disorder (ClinVar).

SETD1A p.Ser963=

Q: How common is SETD1A p.Ser963= (c.2889C>T) in the general population?

SETD1A p.Ser963= (c.2889C>T) is common (popmax 14.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2889C>T · VCV3352507

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 14.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

SETD1A-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 -4.7	GERP -5.4
Overall
CADD	3.317	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.5% East Asian · 6,506/44,818 alleles

Filtering AF 14.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.1%

Overall 0.502% 8,099/1,613,596 alleles · common exomes 7,245/1,461,334 · genomes 854/152,262 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	14.5%	7
Admixed American	1.48%	68
Remaining individualsnot grpmax-eligible	0.506%	198
Ashkenazi Jewishnot grpmax-eligible	0.22%	455
Middle Eastern	0.099%	1,010
Finnishnot grpmax-eligible	0.0828%	1,208
South Asian	0.0769%	1,300
African / African-American	0.0293%	3,411
European (non-Finnish)	0.0147%	6,780

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: SETD1A
Protein: p.Ser963=
Coding: c.2889C>T
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30969423 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 963: the 'disordered' region; a UniProt-annotated variant site (in nedsid)

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SETD1A-related disorder

Similar variants

SETD1A p.Leu669Phe Uncertain significance ★★ ⚠ same condition
SETD1A p.Pro449Ala Uncertain significance ★★ ⚠ same condition
SETD1A p.Cys1697Arg Likely pathogenic ★ same condition
SETD1A p.Glu1345Ter Likely pathogenic ★ same condition
SETD1A p.Glu982Ter Pathogenic ★ same condition
SETD1A c.247-2A>C Uncertain significance ★ same condition
SETD1A p.Ala472Val Uncertain significance ★ ⚠ same condition
SETD1A p.Gly1139Glu 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/setd1a-p-ser963 (accessed [today's date]).

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