Is SETD2 p.Val753Ala (c.2258T>C) pathogenic?

SETD2 p.Val753Ala (c.2258T>C) is classified Likely benign in SETD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1195); Very rare (popmax 0.000254%, nfe).

How common is SETD2 p.Val753Ala (c.2258T>C) in the general population?

SETD2 p.Val753Ala (c.2258T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Val753Ala (c.2258T>C)?

AlphaMissense predicts likely benign (score 0.1195) — an in-silico prediction, not a clinical call.

SETD2 p.Val753Ala

c.2258T>C · VCV3910292

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1195 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1195	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.29, phastCons 0.006
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	15.3	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 0.000254% European (non-Finnish) · 3/1,179,990 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,016 alleles · very rare exomes 2/1,461,774 · genomes 1/152,242 · 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.Val753Ala
Coding: c.2258T>C
MANE Select: NM_014159
Type: single nucleotide variant
Location: chr3:47122378 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 753: 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

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-val753ala (accessed [today's date]).

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