Is SETD1B p.Pro1588Ser (c.4762C>T) pathogenic?

SETD1B p.Pro1588Ser (c.4762C>T) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: likely benign (0.1495); Very rare (popmax 0.00905%, amr); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro1588Ser (c.4762C>T)?

SETD1B p.Pro1588Ser (c.4762C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro1588Ser (c.4762C>T) in the general population?

SETD1B p.Pro1588Ser (c.4762C>T) is very rare (popmax 0.00905%, amr) (gnomAD).

What do computational predictors say about SETD1B p.Pro1588Ser (c.4762C>T)?

AlphaMissense predicts likely benign (score 0.1495) — an in-silico prediction, not a clinical call.

SETD1B p.Pro1588Ser

c.4762C>T · rs1429151951 · VCV2603108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00905%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1495	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00905% Admixed American · 4/44,202 alleles

Filtering AF 0.00301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00182%

Overall 0.00205% 18/877,232 alleles · very rare exomes 17/736,308 · genomes 1/140,924 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00905%	11,051
European (non-Finnish)	0.00235%	42,494

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.Pro1588Ser
Coding: c.4762C>T
MANE Select: NM_001353345
dbSNP: rs1429151951
Type: single nucleotide variant
Location: chr12:121823341 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1588: the 'disordered' region; a UniProt-annotated variant site (in iddseld)

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-pro1588ser (accessed [today's date]).

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