Is SETD1B p.Pro1334Arg (c.4001C>G) pathogenic?

SETD1B p.Pro1334Arg (c.4001C>G) is classified Likely benign in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely benign (0.1556); Low-frequency (popmax 1.12%, sas).

How common is SETD1B p.Pro1334Arg (c.4001C>G) in the general population?

SETD1B p.Pro1334Arg (c.4001C>G) is low-frequency (popmax 1.12%, sas) (gnomAD).

What do computational predictors say about SETD1B p.Pro1334Arg (c.4001C>G)?

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

SETD1B p.Pro1334Arg

c.4001C>G · VCV4919002

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1556 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1556	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -8.82	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 3.7	GERP 1.5, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	18.19	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 1.12% South Asian · 939/84,050 alleles

Filtering AF 1.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.03%

Overall 0.0639% 992/1,551,466 alleles · low-frequency exomes 936/1,399,276 · genomes 56/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.12%	90
Remaining individualsnot grpmax-eligible	0.0715%	1,398
Middle Eastern	0.0334%	2,995
East Asian	0.00244%	40,906
African / African-American	0.00137%	73,136
European (non-Finnish)	0.000523%	191,144

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.Pro1334Arg
Coding: c.4001C>G
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121822580 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1334: 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-pro1334arg (accessed [today's date]).

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