Is SETD2 p.Arg136Thr (c.407G>C) pathogenic?

SETD2 p.Arg136Thr (c.407G>C) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-27). AlphaMissense: ambiguous (0.3516); Rare (popmax 0.12%, eas); Associated with congenital portosystemic shunt.

What condition is associated with SETD2 p.Arg136Thr (c.407G>C)?

SETD2 p.Arg136Thr (c.407G>C) is associated with congenital portosystemic shunt (ClinVar).

How common is SETD2 p.Arg136Thr (c.407G>C) in the general population?

SETD2 p.Arg136Thr (c.407G>C) is rare (popmax 0.12%, eas) (gnomAD).

What do computational predictors say about SETD2 p.Arg136Thr (c.407G>C)?

AlphaMissense predicts ambiguous (score 0.3516) — an in-silico prediction, not a clinical call.

SETD2 p.Arg136Thr

c.407G>C · VCV4813096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3516 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, eas)

Conditions

congenital portosystemic shunt

Computational evidence

Protein change
AlphaMissense	0.3516	ambiguous
REVEL	0.298	indeterminate
SaProt	LLR -5.23	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	24.0	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 0.12% East Asian · 49/40,928 alleles

Filtering AF 0.093% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0835%

Overall 0.00322% 50/1,551,768 alleles · rare exomes 48/1,399,446 · genomes 2/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.12%	835
Remaining individualsnot grpmax-eligible	0.00166%	60,128

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.Arg136Thr
Coding: c.407G>C
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47124229 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 136: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation)

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital portosystemic shunt — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 p.Arg136Ser Uncertain significance ⚠ same residue
SETD2 p.Ser403Asn Uncertain significance ★ ⚠ same condition
SETD2 p.Thr2421Ala Conflicting classifications of pathogenicity ★ ⚠ same condition
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

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-arg136thr (accessed [today's date]).

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