Is SETD1A p.Thr1122= (c.3366G>A) pathogenic?

SETD1A p.Thr1122= (c.3366G>A) is classified Likely benign in SETD1A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-01-09). Ultra-rare (popmax 0.0405%, nfe); Associated with SETD1A-related disorder.

What condition is associated with SETD1A p.Thr1122= (c.3366G>A)?

SETD1A p.Thr1122= (c.3366G>A) is associated with SETD1A-related disorder (ClinVar).

How common is SETD1A p.Thr1122= (c.3366G>A) in the general population?

SETD1A p.Thr1122= (c.3366G>A) is ultra-rare (popmax 0.0405%, nfe) (gnomAD).

SETD1A p.Thr1122=

c.3366G>A · rs367918838 · VCV3055093

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0405%, nfe)

Conditions

SETD1A-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 -5.1	GERP -4.4
Overall
CADD	0.107	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0405% European (non-Finnish) · 468/1,156,292 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0362%

Overall 0.0308% 482/1,566,240 alleles · ultra-rare exomes 458/1,413,986 · genomes 24/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0405%	2,471
Middle Eastern	0.0227%	4,412
Remaining individualsnot grpmax-eligible	0.00827%	12,095
Admixed American	0.00554%	18,049
African / African-American	0.0054%	18,528
Finnishnot grpmax-eligible	0.00166%	60,210

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.Thr1122=
Coding: c.3366G>A
MANE Select: NM_014712
dbSNP: rs367918838
Type: single nucleotide variant
Location: chr16:30979152 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 1122: 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-thr1122 (accessed [today's date]).

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