Is SETD1B p.Arg423Cys (c.1267C>T) pathogenic?

SETD1B p.Arg423Cys (c.1267C>T) is classified Likely benign in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). AlphaMissense: likely benign (0.2813); Ultra-rare (popmax 0.0122%, eas).

How common is SETD1B p.Arg423Cys (c.1267C>T) in the general population?

SETD1B p.Arg423Cys (c.1267C>T) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

What do computational predictors say about SETD1B p.Arg423Cys (c.1267C>T)?

AlphaMissense predicts likely benign (score 0.2813) — an in-silico prediction, not a clinical call.

SETD1B p.Arg423Cys

c.1267C>T · VCV4918933

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2813	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -7.91	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 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 795 bp · p 0.65 · regional, not allelic
Overall
CADD	25.1	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 0.0122% East Asian · 5/40,904 alleles

Filtering AF 0.00479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00194% 30/1,549,418 alleles · ultra-rare exomes 28/1,397,236 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0122%	8,181
South Asian	0.00476%	21,011
African / African-American	0.00411%	24,344
Finnishnot grpmax-eligible	0.00345%	28,987
Admixed American	0.00196%	50,974
European (non-Finnish)	0.00131%	76,458

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.Arg423Cys
Coding: c.1267C>T
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121810212 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 423: the 'disordered' region

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

Similar variants

SETD1B p.Arg423= Likely benign ★ same residue
SETD1B p.Arg423His 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

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-arg423cys (accessed [today's date]).

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