Is SETD2 p.Arg1229Ser (c.3687A>T) pathogenic?

SETD2 p.Arg1229Ser (c.3687A>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: ambiguous (0.4857); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Arg1229Ser (c.3687A>T)?

SETD2 p.Arg1229Ser (c.3687A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD2 p.Arg1229Ser (c.3687A>T) in the general population?

SETD2 p.Arg1229Ser (c.3687A>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SETD2 p.Arg1229Ser (c.3687A>T)?

AlphaMissense predicts ambiguous (score 0.4857) — an in-silico prediction, not a clinical call.

SETD2 p.Arg1229Ser

c.3687A>T · VCV4163173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4857 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4857	ambiguous
REVEL	0.312	indeterminate
SaProt	LLR -4.64	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	20.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000186% 3/1,614,198 alleles · ultra-rare exomes 3/1,461,864 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	8.47e-05%	1,180,016

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.Arg1229Ser
Coding: c.3687A>T
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47120949 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1229: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); the 'disordered' region; a UniProt-annotated variant site (in all; uncertain significance; somatic mutation)

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 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
SETD2 p.Asn840Ser Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp1169Gly Uncertain significance ★★ ⚠ same condition
SETD2 p.Asp294Val 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-arg1229ser (accessed [today's date]).

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