Is SETD1B p.Pro1439Ala (c.4315C>G) pathogenic?

SETD1B p.Pro1439Ala (c.4315C>G) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0604); Very rare (popmax 8.96e-05%, nfe); Associated with intellectual developmental disorder with seizures and language delay.

What condition is associated with SETD1B p.Pro1439Ala (c.4315C>G)?

SETD1B p.Pro1439Ala (c.4315C>G) is associated with intellectual developmental disorder with seizures and language delay (ClinVar).

How common is SETD1B p.Pro1439Ala (c.4315C>G) in the general population?

SETD1B p.Pro1439Ala (c.4315C>G) is very rare (popmax 8.96e-05%, nfe) (gnomAD).

What do computational predictors say about SETD1B p.Pro1439Ala (c.4315C>G)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

SETD1B p.Pro1439Ala

c.4315C>G · rs2137578401 · VCV1339943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.96e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with seizures and language delay

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.42	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 2	GERP -0.75, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	8.291	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 8.96e-05% European (non-Finnish) · 1/1,115,710 alleles

Overall 6.7e-05% 1/1,492,230 alleles · very rare exomes 1/1,339,928 · genomes 0/152,302 · 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.Pro1439Ala
Coding: c.4315C>G
MANE Select: NM_001353345
dbSNP: rs2137578401
Type: single nucleotide variant
Location: chr12:121822894 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1439: a UniProt-annotated variant site (in iddseld); the 'disordered' region

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with seizures and language delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro1439ala (accessed [today's date]).

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