Is SETD1B p.Pro282Ala (c.844C>G) pathogenic?

SETD1B p.Pro282Ala (c.844C>G) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.7444); Very rare (popmax 0.00274%, afr).

How common is SETD1B p.Pro282Ala (c.844C>G) in the general population?

SETD1B p.Pro282Ala (c.844C>G) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about SETD1B p.Pro282Ala (c.844C>G)?

AlphaMissense predicts likely pathogenic (score 0.7444) — an in-silico prediction, not a clinical call.

SETD1B p.Pro282Ala

c.844C>G · VCV3900153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7444 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7444	likely pathogenic
REVEL	0.652	pathogenic-leaning
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 795 bp · p 0.65 · regional, not allelic
Overall
CADD	25.7	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 0.00274% African / African-American · 2/73,038 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000129% 2/1,551,462 alleles · very rare exomes 1/1,399,288 · genomes 1/152,174 · 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.Pro282Ala
Coding: c.844C>G
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121809789 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 282: the 'disordered' region

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-pro282ala (accessed [today's date]).

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