Is SETD2 p.Asp431Tyr (c.1291G>T) pathogenic?

SETD2 p.Asp431Tyr (c.1291G>T) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: likely pathogenic (0.5676); Very rare (popmax 0.00119%, sas).

How common is SETD2 p.Asp431Tyr (c.1291G>T) in the general population?

SETD2 p.Asp431Tyr (c.1291G>T) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about SETD2 p.Asp431Tyr (c.1291G>T)?

AlphaMissense predicts likely pathogenic (score 0.5676) — an in-silico prediction, not a clinical call.

SETD2 p.Asp431Tyr

c.1291G>T · VCV3903150

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5676	likely pathogenic
REVEL	0.298	indeterminate
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
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	24.8	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 0.00119% South Asian · 1/84,058 alleles

Overall 6.44e-05% 1/1,551,680 alleles · very rare exomes 1/1,399,394 · genomes 0/152,286 · 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: SETD2
Protein: p.Asp431Tyr
Coding: c.1291G>T
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47123345 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 431: 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

Similar variants

SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same type
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same type
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same type
SETD2 p.Arg441Ter Likely pathogenic ★★ same type
SETD2 p.Glu1718Lys Likely pathogenic ★★ ⚠ same type
SETD2 c.4715+5G>A Uncertain significance ★★ same type
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same type
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ 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/setd2-p-asp431tyr (accessed [today's date]).

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