Is SETD2 p.Ser131= (c.393C>T) pathogenic?

SETD2 p.Ser131= (c.393C>T) is classified Likely benign in SETD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-20). Very rare (popmax 0.00863%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ser131= (c.393C>T)?

SETD2 p.Ser131= (c.393C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser131= (c.393C>T) in the general population?

SETD2 p.Ser131= (c.393C>T) is very rare (popmax 0.00863%, nfe) (gnomAD).

SETD2 p.Ser131=

c.393C>T · rs556549304 · VCV1155760

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00863%, nfe)

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.68	GERP -4.6, phastCons 0.001
Overall
CADD	2.861	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00863% European (non-Finnish) · 99/1,146,958 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0067%

Overall 0.0067% 104/1,551,668 alleles · very rare exomes 95/1,399,392 · genomes 9/152,276 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00863%	11,585
Remaining individualsnot grpmax-eligible	0.00665%	15,031
Admixed American	0.00196%	51,000

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.Ser131=
Coding: c.393C>T
MANE Select: NM_014159
dbSNP: rs556549304
Type: single nucleotide variant
Location: chr3:47124243 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 131: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a modified residue (phosphoserine)

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.Ser131Tyr Uncertain significance ★ ⚠ same residue
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

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-ser131 (accessed [today's date]).

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