Is SETD1B p.Arg555Trp (c.1663C>T) pathogenic?

SETD1B p.Arg555Trp (c.1663C>T) is classified Pathogenic in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). AlphaMissense: likely benign (0.1556); Very rare (popmax 6.46e-05%).

How common is SETD1B p.Arg555Trp (c.1663C>T) in the general population?

SETD1B p.Arg555Trp (c.1663C>T) is very rare (popmax 6.46e-05%) (gnomAD).

What do computational predictors say about SETD1B p.Arg555Trp (c.1663C>T)?

AlphaMissense predicts likely benign (score 0.1556) — an in-silico prediction, not a clinical call.

SETD1B p.Arg555Trp

c.1663C>T · VCV3390637

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.46e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1556	likely benign ⚠ discordant with ClinVar
REVEL	0.461	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.63, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	21.2	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 6.46e-05%

Overall 6.46e-05% 1/1,548,352 alleles · very rare exomes 1/1,396,040 · genomes 0/152,312 · 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.Arg555Trp
Coding: c.1663C>T
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121810608 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 555: the 'disordered' region

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

Similar variants

SETD1B p.Arg555Gln Likely benign ★ same residue
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

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-arg555trp (accessed [today's date]).

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