Is SETD2 p.Ser249Phe (c.746C>T) pathogenic?

SETD2 p.Ser249Phe (c.746C>T) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-01-05). AlphaMissense: likely benign (0.1206); Very rare (popmax 0.00331%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ser249Phe (c.746C>T)?

SETD2 p.Ser249Phe (c.746C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser249Phe (c.746C>T) in the general population?

SETD2 p.Ser249Phe (c.746C>T) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Ser249Phe (c.746C>T)?

AlphaMissense predicts likely benign (score 0.1206) — an in-silico prediction, not a clinical call.

SETD2 p.Ser249Phe

c.746C>T · rs1162661952 · VCV1805034

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1206 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1206	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -8.71	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 7.4	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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% European (non-Finnish) · 38/1,146,906 alleles

Filtering AF 0.00246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00216%

Overall 0.00251% 39/1,551,858 alleles · very rare exomes 36/1,399,666 · genomes 3/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00331%	30,182
Remaining individualsnot grpmax-eligible	0.00166%	60,274

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.Ser249Phe
Coding: c.746C>T
MANE Select: NM_014159
dbSNP: rs1162661952
Type: single nucleotide variant
Location: chr3:47123890 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 249: 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-ser249phe (accessed [today's date]).

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