Is STAT6 p.Arg536Trp (c.1606C>T) pathogenic?

STAT6 p.Arg536Trp (c.1606C>T) is classified Uncertain significance in STAT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: likely pathogenic (0.607); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with STAT6 p.Arg536Trp (c.1606C>T)?

STAT6 p.Arg536Trp (c.1606C>T) is associated with Inborn genetic diseases (ClinVar).

How common is STAT6 p.Arg536Trp (c.1606C>T) in the general population?

STAT6 p.Arg536Trp (c.1606C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about STAT6 p.Arg536Trp (c.1606C>T)?

AlphaMissense predicts likely pathogenic (score 0.607) — an in-silico prediction, not a clinical call.

STAT6 p.Arg536Trp

c.1606C>T · VCV3450434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.607	likely pathogenic
REVEL	0.675	pathogenic-leaning
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,635 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	27.3	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00093% 15/1,613,496 alleles · ultra-rare exomes 13/1,461,324 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0033%	30,329
East Asian	0.00223%	44,868
Admixed American	0.00167%	59,888
African / African-American	0.00134%	74,902
European (non-Finnish)	0.000678%	147,474

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: STAT6
Protein: p.Arg536Trp
Coding: c.1606C>T
MANE Select: NM_003153
Type: single nucleotide variant
Location: chr12:57099997 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.56 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 7 PDB
Residue 536: the sh2 domain

Full STAT6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STAT6 p.Arg536Gly Uncertain significance ★ ⚠ same residue
STAT6 p.Ala109Val Uncertain significance ★ ⚠ same condition
STAT6 p.Ala245Val Uncertain significance ★ ⚠ same condition
STAT6 p.Ala304Asp Uncertain significance ★ ⚠ same condition
STAT6 p.Ala358Val Uncertain significance ★ ⚠ same condition
STAT6 p.Ala385Thr Uncertain significance ★ same condition
STAT6 p.Ala753Thr Uncertain significance ★ ⚠ same condition
STAT6 p.Ala779Val 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/stat6-p-arg536trp (accessed [today's date]).

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