Is SETD1B p.Arg423His (c.1268G>A) pathogenic?

SETD1B p.Arg423His (c.1268G>A) is classified Likely benign in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely benign (0.1513); Very rare (popmax 0.00411%, afr).

How common is SETD1B p.Arg423His (c.1268G>A) in the general population?

SETD1B p.Arg423His (c.1268G>A) is very rare (popmax 0.00411%, afr) (gnomAD).

What do computational predictors say about SETD1B p.Arg423His (c.1268G>A)?

AlphaMissense predicts likely benign (score 0.1513) — an in-silico prediction, not a clinical call.

SETD1B p.Arg423His

c.1268G>A · VCV3389303

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00411%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1513	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 795 bp · p 0.65 · regional, not allelic
Overall
CADD	22.6	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 0.00411% African / African-American · 3/72,966 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000503%

Overall 0.00071% 11/1,549,158 alleles · very rare exomes 8/1,397,140 · genomes 3/152,018 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00411%	24,322
South Asian	0.00238%	42,021
Admixed American	0.00196%	50,964
Remaining individualsnot grpmax-eligible	0.00167%	60,056
European (non-Finnish)	0.000349%	286,711

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.Arg423His
Coding: c.1268G>A
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121810213 (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.Arg423Cys 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-arg423his (accessed [today's date]).

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