Is SETD2 p.Val2554Ile (c.7660G>A) pathogenic?

SETD2 p.Val2554Ile (c.7660G>A) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-06-20). AlphaMissense: likely benign (0.0714); Very rare (popmax 0.00667%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Val2554Ile (c.7660G>A)?

SETD2 p.Val2554Ile (c.7660G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Val2554Ile (c.7660G>A) in the general population?

SETD2 p.Val2554Ile (c.7660G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Val2554Ile (c.7660G>A)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

SETD2 p.Val2554Ile

c.7660G>A · rs768564000 · VCV939173

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.96	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 1.1	GERP 1.5, phastCons 0.99
Regional constraint	o/e 0.62	unconstrained · MANE · 124 bp · p 0.0095 · regional, not allelic
Overall
CADD	19.32	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 0.00667% Admixed American · 4/60,012 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00223% 36/1,614,082 alleles · very rare exomes 32/1,461,874 · genomes 4/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,003
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00237%	42,145

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.Val2554Ile
Coding: c.7660G>A
MANE Select: NM_014159
dbSNP: rs768564000
Type: single nucleotide variant
Location: chr3:47017128 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 2554: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); a UniProt-annotated variant site (in all; uncertain significance; somatic mutation); the 'interaction with polr2a' region

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-val2554ile (accessed [today's date]).

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