Is SETD1B p.Pro1583= (c.4749A>C) pathogenic?

SETD1B p.Pro1583= (c.4749A>C) is classified Likely benign in SETD1B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-01). Rare (popmax 0.25%, afr).

How common is SETD1B p.Pro1583= (c.4749A>C) in the general population?

SETD1B p.Pro1583= (c.4749A>C) is rare (popmax 0.25%, afr) (gnomAD).

SETD1B p.Pro1583=

c.4749A>C · rs1592988818 · VCV2672528

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.25%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	0.531	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.25% African / African-American · 92/36,804 alleles

Filtering AF 0.236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.212% 1,635/770,780 alleles · rare exomes 1,502/691,322 · genomes 133/79,458 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.278%	360
African / African-Americangrpmax	0.25%	400
European (non-Finnish)	0.247%	405
Middle Eastern	0.146%	685
East Asian	0.0926%	1,080
Ashkenazi Jewishnot grpmax-eligible	0.0864%	1,157
South Asian	0.0656%	1,525
Finnishnot grpmax-eligible	0.0584%	1,712
Admixed American	0.0566%	1,768

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.Pro1583=
Coding: c.4749A>C
MANE Select: NM_001353345
dbSNP: rs1592988818
Type: single nucleotide variant
Location: chr12:121823328 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1583: the 'disordered' region; a UniProt-annotated variant site (in iddseld)

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1B p.Arg1329Ter Pathogenic ★★ same type
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SETD1B p.Arg1825Trp Likely pathogenic ★★ same type
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Gln780Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Glu1948Lys Pathogenic/Likely pathogenic ★★ same type

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-pro1583 (accessed [today's date]).

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