Is SETD1B p.Ser536Ala (c.1606T>G) pathogenic?

SETD1B p.Ser536Ala (c.1606T>G) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: ambiguous (0.3425); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Ser536Ala (c.1606T>G)?

SETD1B p.Ser536Ala (c.1606T>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Ser536Ala (c.1606T>G) in the general population?

SETD1B p.Ser536Ala (c.1606T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD1B p.Ser536Ala (c.1606T>G)?

AlphaMissense predicts ambiguous (score 0.3425) — an in-silico prediction, not a clinical call.

SETD1B p.Ser536Ala

c.1606T>G · rs2500187121 · VCV2531243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3425 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3425	ambiguous
REVEL	0.531	indeterminate
SaProt	LLR -7.15	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.82, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	24.2	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: SETD1B
Protein: p.Ser536Ala
Coding: c.1606T>G
MANE Select: NM_001353345
dbSNP: rs2500187121
Type: single nucleotide variant
Location: chr12:121810551 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 536: the 'disordered' region

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-ser536ala (accessed [today's date]).

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