Is SETD2 p.Arg432His (c.1295G>A) pathogenic?

SETD2 p.Arg432His (c.1295G>A) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.2591); Ultra-rare (popmax 0.0274%, sas); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Arg432His (c.1295G>A)?

SETD2 p.Arg432His (c.1295G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETD2 p.Arg432His (c.1295G>A) in the general population?

SETD2 p.Arg432His (c.1295G>A) is ultra-rare (popmax 0.0274%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Arg432His (c.1295G>A)?

AlphaMissense predicts likely benign (score 0.2591) — an in-silico prediction, not a clinical call.

SETD2 p.Arg432His

c.1295G>A · rs762208680 · VCV2623819

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0274%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2591	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	26.4	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 0.0274% South Asian · 23/84,064 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.00238% 37/1,551,522 alleles · ultra-rare exomes 36/1,399,412 · genomes 1/152,110 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0274%	3,655
East Asian	0.0171%	5,847
Finnishnot grpmax-eligible	0.00334%	29,939
Remaining individualsnot grpmax-eligible	0.00333%	30,050
Admixed American	0.00196%	50,970
European (non-Finnish)	0.000174%	573,500

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.Arg432His
Coding: c.1295G>A
MANE Select: NM_014159
dbSNP: rs762208680
Type: single nucleotide variant
Location: chr3:47123341 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 432: 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 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-arg432his (accessed [today's date]).

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