Is SETD2 p.Pro1141Leu (c.3422C>T) pathogenic?

SETD2 p.Pro1141Leu (c.3422C>T) is classified Benign/Likely benign in SETD2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-15). AlphaMissense: likely benign (0.0725); Rare (popmax 0.127%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Pro1141Leu (c.3422C>T)?

SETD2 p.Pro1141Leu (c.3422C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Pro1141Leu (c.3422C>T) in the general population?

SETD2 p.Pro1141Leu (c.3422C>T) is rare (popmax 0.127%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Pro1141Leu (c.3422C>T)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

SETD2 p.Pro1141Leu

c.3422C>T · rs142723093 · VCV475512

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.127%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.31	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 1.3	GERP -3, phastCons 0.014
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	11.58	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 0.127% European (non-Finnish) · 1,495/1,179,966 alleles

Filtering AF 0.121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.119%

Overall 0.102% 1,649/1,613,986 alleles · rare exomes 1,518/1,461,816 · genomes 131/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.127%	789
Admixed American	0.0783%	1,276
Remaining individualsnot grpmax-eligible	0.064%	1,563
Ashkenazi Jewishnot grpmax-eligible	0.054%	1,850
Finnishnot grpmax-eligible	0.0359%	2,782
African / African-American	0.0213%	4,688
Middle Eastern	0.0165%	6,062
South Asian	0.0121%	8,278

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.Pro1141Leu
Coding: c.3422C>T
MANE Select: NM_014159
dbSNP: rs142723093
Type: single nucleotide variant
Location: chr3:47121214 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1141: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); the 'disordered' region; a UniProt-annotated variant site (in all; 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-pro1141leu (accessed [today's date]).

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