Is SETD1B p.Ser1096Phe (c.3287C>T) pathogenic?

SETD1B p.Ser1096Phe (c.3287C>T) is classified Likely benign in SETD1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.1277); Ultra-rare (popmax 0.0131%, sas).

How common is SETD1B p.Ser1096Phe (c.3287C>T) in the general population?

SETD1B p.Ser1096Phe (c.3287C>T) is ultra-rare (popmax 0.0131%, sas) (gnomAD).

What do computational predictors say about SETD1B p.Ser1096Phe (c.3287C>T)?

AlphaMissense predicts likely benign (score 0.1277) — an in-silico prediction, not a clinical call.

SETD1B p.Ser1096Phe

c.3287C>T · VCV3911005

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.1277	likely benign
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 0.18, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0131% South Asian · 11/84,038 alleles

Filtering AF 0.0073% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00561%

Overall 0.00606% 94/1,549,928 alleles · ultra-rare exomes 85/1,397,728 · genomes 9/152,200 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0131%	7,640
European (non-Finnish)	0.00698%	14,326
Remaining individualsnot grpmax-eligible	0.00333%	30,013
Finnishnot grpmax-eligible	0.00169%	59,336

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.Ser1096Phe
Coding: c.3287C>T
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121817679 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1096: a UniProt-annotated variant site (in iddseld); the 'disordered' region

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

Similar variants

SETD1B p.Arg1329Ter Pathogenic ★★ same type
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SETD1B p.Arg1825Trp Likely pathogenic ★★ same type
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Gln780Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Glu1948Lys Pathogenic/Likely pathogenic ★★ 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/setd1b-p-ser1096phe (accessed [today's date]).

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