Is SETD2 p.Ser112Leu (c.335C>T) pathogenic?

SETD2 p.Ser112Leu (c.335C>T) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-23). AlphaMissense: likely benign (0.0696); Ultra-rare (popmax 0.0724%, afr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ser112Leu (c.335C>T)?

SETD2 p.Ser112Leu (c.335C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser112Leu (c.335C>T) in the general population?

SETD2 p.Ser112Leu (c.335C>T) is ultra-rare (popmax 0.0724%, afr) (gnomAD).

What do computational predictors say about SETD2 p.Ser112Leu (c.335C>T)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

SETD2 p.Ser112Leu

c.335C>T · rs187767340 · VCV475508

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0724%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.13	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 2.5	GERP -1.8, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	14.69	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 0.0724% African / African-American · 53/73,166 alleles

Filtering AF 0.0568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0513%

Overall 0.00393% 61/1,551,744 alleles · ultra-rare exomes 31/1,399,430 · genomes 30/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0724%	1,380
Middle Eastern	0.0334%	2,996
Admixed American	0.00588%	17,001
Remaining individualsnot grpmax-eligible	0.00333%	30,063
European (non-Finnish)	8.72e-05%	1,146,982

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.Ser112Leu
Coding: c.335C>T
MANE Select: NM_014159
dbSNP: rs187767340
Type: single nucleotide variant
Location: chr3:47124301 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 112: 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.Ser112= Likely benign ★ same residue
SETD2 p.Ser112Ala 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

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-ser112leu (accessed [today's date]).

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