Is SETD2 p.Lys629Glu (c.1885A>G) pathogenic?

SETD2 p.Lys629Glu (c.1885A>G) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.1269); Ultra-rare (popmax 0.0813%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Lys629Glu (c.1885A>G)?

SETD2 p.Lys629Glu (c.1885A>G) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Lys629Glu (c.1885A>G) in the general population?

SETD2 p.Lys629Glu (c.1885A>G) is ultra-rare (popmax 0.0813%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Lys629Glu (c.1885A>G)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

SETD2 p.Lys629Glu

c.1885A>G · rs145650484 · VCV542227

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0813%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -6.70	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	23.5	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 0.0813% European (non-Finnish) · 959/1,179,106 alleles

Filtering AF 0.0771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0753%

Overall 0.062% 998/1,610,826 alleles · ultra-rare exomes 931/1,458,602 · genomes 67/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0813%	1,230
Remaining individualsnot grpmax-eligible	0.0385%	2,596
African / African-American	0.0121%	8,291
Admixed American	0.00844%	11,843
Finnishnot grpmax-eligible	0.00157%	63,722

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.Lys629Glu
Coding: c.1885A>G
MANE Select: NM_014159
dbSNP: rs145650484
Type: single nucleotide variant
Location: chr3:47122751 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 629: 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-lys629glu (accessed [today's date]).

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