Is SETD2 p.Val137Met (c.409G>A) pathogenic?

SETD2 p.Val137Met (c.409G>A) is classified Uncertain significance in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely benign (0.2796); Very rare (popmax 0.00411%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Val137Met (c.409G>A)?

SETD2 p.Val137Met (c.409G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Val137Met (c.409G>A) in the general population?

SETD2 p.Val137Met (c.409G>A) is very rare (popmax 0.00411%, afr) (gnomAD).

What do computational predictors say about SETD2 p.Val137Met (c.409G>A)?

AlphaMissense predicts likely benign (score 0.2796) — an in-silico prediction, not a clinical call.

SETD2 p.Val137Met

c.409G>A · rs886565042 · VCV2870337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00411%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.2796	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -7.49	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 3.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00411% African / African-American · 3/73,050 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000502%

Overall 0.000322% 5/1,551,650 alleles · very rare exomes 4/1,399,456 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00411%	24,350
Admixed American	0.00196%	50,984
Remaining individualsnot grpmax-eligible	0.00166%	60,106

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.Val137Met
Coding: c.409G>A
MANE Select: NM_014159
dbSNP: rs886565042
Type: single nucleotide variant
Location: chr3:47124227 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 137: 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

Luscan-Lumish syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys Uncertain significance ★★ same condition
SETD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg368Gln 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-val137met (accessed [today's date]).

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