Is SETD2 p.Ser742Ala (c.2224T>G) pathogenic?

SETD2 p.Ser742Ala (c.2224T>G) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-14). AlphaMissense: likely benign (0.0669); Ultra-rare (popmax 0.0317%, amr); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Ser742Ala (c.2224T>G)?

SETD2 p.Ser742Ala (c.2224T>G) is associated with Inborn genetic diseases, Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser742Ala (c.2224T>G) in the general population?

SETD2 p.Ser742Ala (c.2224T>G) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Ser742Ala (c.2224T>G)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

SETD2 p.Ser742Ala

c.2224T>G · rs774644234 · VCV542219

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -7.25	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 4	GERP -0.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	14.66	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 0.0317% Admixed American · 19/59,998 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00124% 20/1,613,974 alleles · ultra-rare exomes 17/1,461,776 · genomes 3/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Ser742Ala
Coding: c.2224T>G
MANE Select: NM_014159
dbSNP: rs774644234
Type: single nucleotide variant
Location: chr3:47122412 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 742: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Luscan-Lumish syndrome

Similar variants

SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same condition
SETD2 c.4715+5G>A Uncertain significance ★★ same condition
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys Uncertain significance ★★ same condition
SETD2 p.Arg1197Thr 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-ser742ala (accessed [today's date]).

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