Is SETD2 p.Pro1226Leu (c.3677C>T) pathogenic?

SETD2 p.Pro1226Leu (c.3677C>T) is classified Likely benign in SETD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-01). AlphaMissense: likely benign (0.1657); Very rare (popmax 0.00441%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Pro1226Leu (c.3677C>T)?

SETD2 p.Pro1226Leu (c.3677C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Pro1226Leu (c.3677C>T) in the general population?

SETD2 p.Pro1226Leu (c.3677C>T) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Pro1226Leu (c.3677C>T)?

AlphaMissense predicts likely benign (score 0.1657) — an in-silico prediction, not a clinical call.

SETD2 p.Pro1226Leu

c.3677C>T · rs776766535 · VCV833639

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1657	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	22.5	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 0.00441% European (non-Finnish) · 52/1,180,014 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00335% 54/1,614,038 alleles · very rare exomes 52/1,461,850 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,693
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Pro1226Leu
Coding: c.3677C>T
MANE Select: NM_014159
dbSNP: rs776766535
Type: single nucleotide variant
Location: chr3:47120959 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1226: 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-pro1226leu (accessed [today's date]).

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