Is SETD1B p.Arg1644Pro (c.4931G>C) pathogenic?

SETD1B p.Arg1644Pro (c.4931G>C) is classified Conflicting classifications of pathogenicity in SETD1B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-27). AlphaMissense: likely pathogenic (0.6971); Very rare (popmax 6.45e-05%); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Arg1644Pro (c.4931G>C)?

SETD1B p.Arg1644Pro (c.4931G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Arg1644Pro (c.4931G>C) in the general population?

SETD1B p.Arg1644Pro (c.4931G>C) is very rare (popmax 6.45e-05%) (gnomAD).

What do computational predictors say about SETD1B p.Arg1644Pro (c.4931G>C)?

AlphaMissense predicts likely pathogenic (score 0.6971) — an in-silico prediction, not a clinical call.

SETD1B p.Arg1644Pro

c.4931G>C · rs1029023191 · VCV2237448

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.45e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6971	likely pathogenic
REVEL	0.686	pathogenic-leaning
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -0.91, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,108 bp · p 0.69 · regional, not allelic
Overall
CADD	24.6	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 6.45e-05%

Overall 6.45e-05% 1/1,550,714 alleles · very rare exomes 1/1,398,516 · genomes 0/152,198 · 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.Arg1644Pro
Coding: c.4931G>C
MANE Select: NM_001353345
dbSNP: rs1029023191
Type: single nucleotide variant
Location: chr12:121823510 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 1644: the 'disordered' region; a UniProt-annotated variant site (in iddseld)

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-arg1644pro (accessed [today's date]).

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