Is SETD1B p.Pro744Leu (c.2231C>T) pathogenic?

SETD1B p.Pro744Leu (c.2231C>T) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: likely benign (0.2732); Very rare (popmax 0.0057%, amr); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro744Leu (c.2231C>T)?

SETD1B p.Pro744Leu (c.2231C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro744Leu (c.2231C>T) in the general population?

SETD1B p.Pro744Leu (c.2231C>T) is very rare (popmax 0.0057%, amr) (gnomAD).

What do computational predictors say about SETD1B p.Pro744Leu (c.2231C>T)?

AlphaMissense predicts likely benign (score 0.2732) — an in-silico prediction, not a clinical call.

SETD1B p.Pro744Leu

c.2231C>T · rs1198689759 · VCV2208612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0057%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2732	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	16.79	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 0.0057% Admixed American · 2/35,110 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.0018% 26/1,445,456 alleles · very rare exomes 18/1,296,702 · genomes 8/148,754 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0057%	17,555
European (non-Finnish)	0.0021%	47,678
Remaining individualsnot grpmax-eligible	0.0018%	55,518

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.Pro744Leu
Coding: c.2231C>T
MANE Select: NM_001353345
dbSNP: rs1198689759
Type: single nucleotide variant
Location: chr12:121814446 (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-pro744leu (accessed [today's date]).

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