Is SETD1B p.Ser1464Pro (c.4390T>C) pathogenic?

SETD1B p.Ser1464Pro (c.4390T>C) is classified Uncertain significance in SETD1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-05). AlphaMissense: likely benign (0.0977); No allele count reported in gnomAD v4.1 (AN 1,536,884); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Ser1464Pro (c.4390T>C)?

SETD1B p.Ser1464Pro (c.4390T>C) is associated with Inborn genetic diseases, intellectual developmental disorder with seizures and language delay (ClinVar).

How common is SETD1B p.Ser1464Pro (c.4390T>C) in the general population?

SETD1B p.Ser1464Pro (c.4390T>C) is no allele count reported in gnomAD v4.1 (AN 1,536,884) (gnomAD).

What do computational predictors say about SETD1B p.Ser1464Pro (c.4390T>C)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

SETD1B p.Ser1464Pro

c.4390T>C · rs2500234011 · VCV2582414

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,536,884)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	22.6	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

No allele count reported in gnomAD v4.1 (AN 1,536,884). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SETD1B
Protein: p.Ser1464Pro
Coding: c.4390T>C
MANE Select: NM_001353345
dbSNP: rs2500234011
Type: single nucleotide variant
Location: chr12:121822969 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1464: 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

Also linked: intellectual developmental disorder with seizures and language delay

Similar variants

SETD1B p.Arg1329Ter Pathogenic ★★ same condition
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETD1B p.Arg1825Trp Likely pathogenic ★★ same condition
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Gln780Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1B p.Glu1948Lys Pathogenic/Likely pathogenic ★★ 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-ser1464pro (accessed [today's date]).

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