# NM_003151.4(STAT4):c.2064G>C (p.Arg688Ser)

https://sugi.bio/variant/stat4-p-arg688ser

## Summary

**STAT4 p.Arg688Ser (c.2064G>C)** is classified **Uncertain significance** in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). AlphaMissense: likely benign (0.1326); Ultra-rare (popmax 0.0201%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs768045385 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the STAT4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAT4](https://sugi.bio/atlas/gene/STAT4/) |
| Protein change (HGVS p.) | p.Arg688Ser |
| Coding change (HGVS c.) | c.2064G>C |
| MANE Select transcript | [NM_003151](https://www.ncbi.nlm.nih.gov/nuccore/NM_003151) |
| dbSNP | [rs768045385](https://www.ncbi.nlm.nih.gov/snp/rs768045385/) |
| Variant type | single nucleotide variant |
| Location | chr2:191031497-191031497 (GRCh38) |
| ClinVar | [VCV1941174](https://www.ncbi.nlm.nih.gov/clinvar/variation/1941174/) |

**All HGVS expressions:** `NC_000002.11:g.191896223C>G`, `NC_000002.12:g.191031497C>G`, `NG_012852.1:g.124703G>C`, `NG_012852.2:g.219678G>C`, `NM_001243835.2:c.2064G>C`, `NM_003151.4:c.2064G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1326)
- REVEL 0.494 (indeterminate)
- SaProt LLR -4.858 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.535, GERP -2.42, phastCons 0.022 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.98**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.15** across the covering region of the MANE Select transcript (191,031,486–191,033,006), spanning 1,520 bp. Chi-square p 0.4. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.25**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**.
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.0078% · 9/44,812 in the highest group · 9/1,613,002 alleles overall — ultra-rare (popmax 0.0201%, eas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**STAT4** population constraint: LOEUF 0.503, pLI 0.93457, missense-Z 3.2053. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.87, 65% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of STAT4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** STAT4's established molecular role includes DNA-binding transcription factor activity.


### Pathways affected {#pathways}

STAT4 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation](https://reactome.org/content/detail/R-HSA-8950505) | curated |
| [Interleukin-20 family signaling](https://reactome.org/content/detail/R-HSA-8854691) | curated |
| [Interleukin-21 signaling](https://reactome.org/content/detail/R-HSA-9020958) | curated |
| [Interleukin-23 signaling](https://reactome.org/content/detail/R-HSA-9020933) | curated |
| [Interleukin-35 Signalling](https://reactome.org/content/detail/R-HSA-8984722) | curated |
| [Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)](https://reactome.org/content/detail/R-HSA-9942503) | electronic |
| [Interleukin-12 signaling](https://reactome.org/content/detail/R-HSA-9020591) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA-binding transcription factor activity, identical protein binding.

**Biological process:** interleukin-12-mediated signaling pathway, T-helper 1 cell differentiation, response to interleukin-6.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-20 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related STAT4 variant pages (same residue, condition, or type): [STAT4 p.Arg688Gly](/variant/stat4-p-arg688gly), [STAT4 p.Ala245Thr](/variant/stat4-p-ala245thr), [STAT4 p.Arg241Gln](/variant/stat4-p-arg241gln), [STAT4 p.Arg70Leu](/variant/stat4-p-arg70leu), [STAT4 p.Arg87Lys](/variant/stat4-p-arg87lys), [STAT4 p.Asp513Val](/variant/stat4-p-asp513val), [STAT4 p.Cys323Arg](/variant/stat4-p-cys323arg), [STAT4 p.Gln243Lys](/variant/stat4-p-gln243lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1941174). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*