Is SETD2 p.Arg441Pro (c.1322G>C) pathogenic?

SETD2 p.Arg441Pro (c.1322G>C) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.7702); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Arg441Pro (c.1322G>C)?

SETD2 p.Arg441Pro (c.1322G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD2 p.Arg441Pro (c.1322G>C) in the general population?

SETD2 p.Arg441Pro (c.1322G>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about SETD2 p.Arg441Pro (c.1322G>C)?

AlphaMissense predicts likely pathogenic (score 0.7702) — an in-silico prediction, not a clinical call.

SETD2 p.Arg441Pro

c.1322G>C · VCV3952849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7702	likely pathogenic
REVEL	0.276	benign-leaning
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	25.3	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 0.0167% Middle Eastern · 1/5,992 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000322% 5/1,551,696 alleles · ultra-rare exomes 5/1,399,494 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,992
Remaining individualsnot grpmax-eligible	0.00166%	60,120
European (non-Finnish)	0.000262%	382,338

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: SETD2
Protein: p.Arg441Pro
Coding: c.1322G>C
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47123314 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 441: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); the 'disordered' region

Full SETD2 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

SETD2 p.Arg441Ter Likely pathogenic ★★ same residue
SETD2 p.Arg441Gln Uncertain significance ★ ⚠ same residue
SETD2 p.Arg441Gly Uncertain significance ★ ⚠ same residue
SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Arg1197Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg540Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Asn1303Ser 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/setd2-p-arg441pro (accessed [today's date]).

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