Is SETD2 p.Ala50Thr (c.148G>A) pathogenic?

SETD2 p.Ala50Thr (c.148G>A) is classified Conflicting classifications of pathogenicity in SETD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-14). AlphaMissense: ambiguous (0.4629); Very rare (popmax 0.00532%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Ala50Thr (c.148G>A)?

SETD2 p.Ala50Thr (c.148G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Ala50Thr (c.148G>A) in the general population?

SETD2 p.Ala50Thr (c.148G>A) is very rare (popmax 0.00532%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Ala50Thr (c.148G>A)?

AlphaMissense predicts ambiguous (score 0.4629) — an in-silico prediction, not a clinical call.

SETD2 p.Ala50Thr

c.148G>A · rs191985301 · VCV542232

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00532%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.4629	ambiguous
REVEL	0.276	benign-leaning
SaProt	LLR -6.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 40 kb · p 0.036 · regional, not allelic
Overall
CADD	24.4	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 0.00532% European (non-Finnish) · 61/1,146,978 alleles

Filtering AF 0.00422% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00638% 99/1,551,736 alleles · very rare exomes 86/1,399,394 · genomes 13/152,342 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0584%	1,712
European (non-Finnish)grpmax	0.00532%	18,803
Admixed American	0.00392%	25,504
Remaining individualsnot grpmax-eligible	0.00166%	60,124

Finnish 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.Ala50Thr
Coding: c.148G>A
MANE Select: NM_014159
dbSNP: rs191985301
Type: single nucleotide variant
Location: chr3:47124488 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB

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-ala50thr (accessed [today's date]).

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