Is SETD2 p.Ile635Val (c.1903A>G) pathogenic?

SETD2 p.Ile635Val (c.1903A>G) is classified Likely benign in SETD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-25). AlphaMissense: likely benign (0.0564); Ultra-rare (popmax 0.0662%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD2 p.Ile635Val (c.1903A>G)?

SETD2 p.Ile635Val (c.1903A>G) is associated with Inborn genetic diseases, Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ile635Val (c.1903A>G) in the general population?

SETD2 p.Ile635Val (c.1903A>G) is ultra-rare (popmax 0.0662%, mid) (gnomAD).

What do computational predictors say about SETD2 p.Ile635Val (c.1903A>G)?

AlphaMissense predicts likely benign (score 0.0564) — an in-silico prediction, not a clinical call.

SETD2 p.Ile635Val

c.1903A>G · rs147609782 · VCV715966

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0564 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0662%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0564	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -5.56	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 -0.42	GERP -4.7, phastCons 0.16
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	1.665	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 0.0662% Middle Eastern · 4/6,038 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00521% 84/1,611,208 alleles · ultra-rare exomes 68/1,458,858 · genomes 16/152,350 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.122%	819
Middle Easterngrpmax	0.0662%	1,510
African / African-American	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.00802%	12,467
East Asian	0.00446%	22,431
European (non-Finnish)	0.00144%	69,353

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile635Val
Coding: c.1903A>G
MANE Select: NM_014159
dbSNP: rs147609782
Type: single nucleotide variant
Location: chr3:47122733 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 635: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Luscan-Lumish syndrome

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 c.4715+5G>A Uncertain significance ★★ 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.Arg1197Thr 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-ile635val (accessed [today's date]).

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