Is SETD1B p.His325= (c.975C>T) pathogenic?

SETD1B p.His325= (c.975C>T) is classified Likely benign in SETD1B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-08). Very rare (popmax 0.00174%, nfe); Associated with SETD1B-related disorder.

What condition is associated with SETD1B p.His325= (c.975C>T)?

SETD1B p.His325= (c.975C>T) is associated with SETD1B-related disorder (ClinVar).

How common is SETD1B p.His325= (c.975C>T) in the general population?

SETD1B p.His325= (c.975C>T) is very rare (popmax 0.00174%, nfe) (gnomAD).

SETD1B p.His325=

c.975C>T · rs972538974 · VCV3041623

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00174%, nfe)

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 -15	GERP -2.9
Overall
CADD	0.284	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% European (non-Finnish) · 20/1,146,984 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000926%

Overall 0.00168% 26/1,551,014 alleles · very rare exomes 25/1,398,880 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00832%	12,017
European (non-Finnish)grpmax	0.00174%	57,349
African / African-American	0.00137%	73,024

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His325=
Coding: c.975C>T
MANE Select: NM_001353345
dbSNP: rs972538974
Type: single nucleotide variant
Location: chr12:121809920 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB

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-his325 (accessed [today's date]).

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