Is SETD2 p.Pro104Thr (c.310C>A) pathogenic?

SETD2 p.Pro104Thr (c.310C>A) is classified Likely benign in SETD2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-07-01). AlphaMissense: likely benign (0.0676); Ultra-rare (popmax 0.0586%, eas); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Pro104Thr (c.310C>A)?

SETD2 p.Pro104Thr (c.310C>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Pro104Thr (c.310C>A) in the general population?

SETD2 p.Pro104Thr (c.310C>A) is ultra-rare (popmax 0.0586%, eas) (gnomAD).

What do computational predictors say about SETD2 p.Pro104Thr (c.310C>A)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

SETD2 p.Pro104Thr

c.310C>A · rs539506462 · VCV135223

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0586%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.12	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 1.9	GERP -0.33, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	15.65	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 0.0586% East Asian · 24/40,926 alleles

Filtering AF 0.0404% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0344%

Overall 0.0018% 28/1,551,740 alleles · ultra-rare exomes 20/1,399,450 · genomes 8/152,290 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0586%	1,705
Remaining individualsnot grpmax-eligible	0.00665%	15,030

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.Pro104Thr
Coding: c.310C>A
MANE Select: NM_014159
dbSNP: rs539506462
Type: single nucleotide variant
Location: chr3:47124326 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 104: 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-pro104thr (accessed [today's date]).

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