Is SETD1A p.Ser290Ile (c.869G>T) pathogenic?

SETD1A p.Ser290Ile (c.869G>T) is classified Likely pathogenic in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.4113); Absent from gnomAD v4.1.

How common is SETD1A p.Ser290Ile (c.869G>T) in the general population?

SETD1A p.Ser290Ile (c.869G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD1A p.Ser290Ile (c.869G>T)?

AlphaMissense predicts ambiguous (score 0.4113) — an in-silico prediction, not a clinical call.

SETD1A p.Ser290Ile

c.869G>T · VCV4755737

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4113 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4113	ambiguous
REVEL	0.424	indeterminate
SaProt	LLR -9.80	tolerated
Splicing
SpliceAI	Δ0.95	donor loss · deltas
Pangolin	Δ0.84	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,694 bp · p 0.44 · regional, not allelic
Overall
CADD	35.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETD1A
Protein: p.Ser290Ile
Coding: c.869G>T
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30964323 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 290: a UniProt-annotated variant site (in nedsid); the 'disordered' region

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1A c.518-2A>G Pathogenic ★★ same type
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg668Ter Pathogenic ★★ same type
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same type
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Tyr646Ter Pathogenic ★★ same type
SETD1A c.4692+3G>A Uncertain significance ★★ 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/setd1a-p-ser290ile (accessed [today's date]).

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