Is SETD1B p.Pro754Thr (c.2260C>A) pathogenic?

SETD1B p.Pro754Thr (c.2260C>A) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: ambiguous (0.4645); Very rare (popmax 9.09e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro754Thr (c.2260C>A)?

SETD1B p.Pro754Thr (c.2260C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro754Thr (c.2260C>A) in the general population?

SETD1B p.Pro754Thr (c.2260C>A) is very rare (popmax 9.09e-05%, nfe) (gnomAD).

What do computational predictors say about SETD1B p.Pro754Thr (c.2260C>A)?

AlphaMissense predicts ambiguous (score 0.4645) — an in-silico prediction, not a clinical call.

SETD1B p.Pro754Thr

c.2260C>A · VCV3317718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.09e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4645	ambiguous
REVEL	0.507	indeterminate
SaProt	LLR -10.76	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.55, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 3,044 bp · p 6e-11 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.09e-05% European (non-Finnish) · 1/1,100,338 alleles

Overall 6.87e-05% 1/1,455,582 alleles · very rare exomes 1/1,305,048 · genomes 0/150,534 · joint denominator

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.Pro754Thr
Coding: c.2260C>A
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121814475 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1B p.Ala1657Val Uncertain significance ★★ ⚠ same condition
SETD1B p.Ala654Thr Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1428Trp Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1458His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1643His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1670Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg467Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Asp1107Asn 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-pro754thr (accessed [today's date]).

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