Is SETD2 p.Phe88Tyr (c.263T>A) pathogenic?

SETD2 p.Phe88Tyr (c.263T>A) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: ambiguous (0.5027); Ultra-rare (popmax 0.0234%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Phe88Tyr (c.263T>A)?

SETD2 p.Phe88Tyr (c.263T>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Phe88Tyr (c.263T>A) in the general population?

SETD2 p.Phe88Tyr (c.263T>A) is ultra-rare (popmax 0.0234%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Phe88Tyr (c.263T>A)?

AlphaMissense predicts ambiguous (score 0.5027) — an in-silico prediction, not a clinical call.

SETD2 p.Phe88Tyr

c.263T>A · rs770312954 · VCV1034625

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, nfe)

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.5027	ambiguous
REVEL	0.423	indeterminate
SaProt	LLR -6.71	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	24.7	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 0.0234% European (non-Finnish) · 268/1,147,050 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.018% 280/1,551,828 alleles · ultra-rare exomes 267/1,399,618 · genomes 13/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0234%	4,280
Remaining individualsnot grpmax-eligible	0.00997%	10,028
African / African-American	0.00685%	14,608
Admixed American	0.00196%	50,982

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.Phe88Tyr
Coding: c.263T>A
MANE Select: NM_014159
dbSNP: rs770312954
Type: single nucleotide variant
Location: chr3:47124373 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 88: 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-phe88tyr (accessed [today's date]).

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