Is STAT6 p.Pro216Gln (c.647C>A) pathogenic?

STAT6 p.Pro216Gln (c.647C>A) is classified Uncertain significance in STAT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1363); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with STAT6 p.Pro216Gln (c.647C>A)?

STAT6 p.Pro216Gln (c.647C>A) is associated with Inborn genetic diseases (ClinVar).

How common is STAT6 p.Pro216Gln (c.647C>A) in the general population?

STAT6 p.Pro216Gln (c.647C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT6 p.Pro216Gln (c.647C>A)?

AlphaMissense predicts likely benign (score 0.1363) — an in-silico prediction, not a clinical call.

STAT6 p.Pro216Gln

c.647C>A · VCV4632377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1363 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1363	likely benign
REVEL	0.469	indeterminate
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP -0.11, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 3,517 bp · p 6e-06 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STAT6
Protein: p.Pro216Gln
Coding: c.647C>A
MANE Select: NM_003153
Type: single nucleotide variant
Location: chr12:57106224 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.56 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 7 PDB

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.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
STAT6 p.Arg115Cys 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-pro216gln (accessed [today's date]).

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