Is SETD1B p.Phe428Leu (c.1282T>C) pathogenic?

SETD1B p.Phe428Leu (c.1282T>C) is classified Likely benign in SETD1B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.9212); Ultra-rare (popmax 0.0397%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Phe428Leu (c.1282T>C)?

SETD1B p.Phe428Leu (c.1282T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Phe428Leu (c.1282T>C) in the general population?

SETD1B p.Phe428Leu (c.1282T>C) is ultra-rare (popmax 0.0397%, nfe) (gnomAD).

What do computational predictors say about SETD1B p.Phe428Leu (c.1282T>C)?

AlphaMissense predicts likely pathogenic (score 0.9212) — an in-silico prediction, not a clinical call.

SETD1B p.Phe428Leu

c.1282T>C · rs772622535 · VCV2387671

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0397%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9212	likely pathogenic
REVEL	0.346	indeterminate
SaProt	LLR -5.20	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 795 bp · p 0.65 · 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

Grpmax group 0.0397% European (non-Finnish) · 455/1,146,594 alleles

Filtering AF 0.0366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0355%

Overall 0.0314% 486/1,547,478 alleles · ultra-rare exomes 461/1,396,584 · genomes 25/150,894 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0397%	2,520
Remaining individualsnot grpmax-eligible	0.0233%	4,289
Admixed American	0.0177%	5,650
South Asian	0.00595%	16,795
African / African-American	0.00414%	24,172

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.Phe428Leu
Coding: c.1282T>C
MANE Select: NM_001353345
dbSNP: rs772622535
Type: single nucleotide variant
Location: chr12:121810227 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 428: 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-phe428leu (accessed [today's date]).

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