Is SETD2 p.Ser1572Leu (c.4715C>T) pathogenic?

SETD2 p.Ser1572Leu (c.4715C>T) is classified Likely benign in SETD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely benign (0.1137); Very rare (popmax 0.00353%, amr); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ser1572Leu (c.4715C>T)?

SETD2 p.Ser1572Leu (c.4715C>T) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ser1572Leu (c.4715C>T) in the general population?

SETD2 p.Ser1572Leu (c.4715C>T) is very rare (popmax 0.00353%, amr) (gnomAD).

What do computational predictors say about SETD2 p.Ser1572Leu (c.4715C>T)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

SETD2 p.Ser1572Leu

c.4715C>T · rs750924110 · VCV715193

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -5.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.3, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 19 kb · p 4.3e-27 · regional, not allelic
Overall
CADD	32.0	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 0.00353% Admixed American · 2/56,726 alleles

Filtering AF 0.000585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000249% 4/1,604,246 alleles · very rare exomes 4/1,452,260 · genomes 0/151,986 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00353%	28,363
South Asian	0.00111%	89,824
European (non-Finnish)	8.5e-05%	1,177,151

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.Ser1572Leu
Coding: c.4715C>T
MANE Select: NM_014159
dbSNP: rs750924110
Type: single nucleotide variant
Location: chr3:47113876 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 1572: 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 tuba1a' region; the set domain

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.Ser1572= Likely benign ★ same residue
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

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-ser1572leu (accessed [today's date]).

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