Is STAT6 p.Leu324Pro (c.971T>C) pathogenic?

STAT6 p.Leu324Pro (c.971T>C) is classified Uncertain significance in STAT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.834); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with STAT6 p.Leu324Pro (c.971T>C)?

STAT6 p.Leu324Pro (c.971T>C) is associated with Inborn genetic diseases (ClinVar).

How common is STAT6 p.Leu324Pro (c.971T>C) in the general population?

STAT6 p.Leu324Pro (c.971T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about STAT6 p.Leu324Pro (c.971T>C)?

AlphaMissense predicts likely pathogenic (score 0.834) — an in-silico prediction, not a clinical call.

STAT6 p.Leu324Pro

c.971T>C · VCV4839328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.834	likely pathogenic
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -14.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 3,517 bp · p 6e-06 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,752 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,378 alleles · very rare exomes 3/1,461,298 · genomes 1/152,080 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,578
European (non-Finnish)grpmax	0.000254%	393,250

Ashkenazi Jewish 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: STAT6
Protein: p.Leu324Pro
Coding: c.971T>C
MANE Select: NM_003153
Type: single nucleotide variant
Location: chr12:57105181 (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-leu324pro (accessed [today's date]).

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