# NM_003151.4(STAT4):c.2110A>G (p.Ile704Val)

https://sugi.bio/variant/stat4-p-ile704val

## Summary

**STAT4 p.Ile704Val (c.2110A>G)** is classified **Uncertain significance** in STAT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-09). AlphaMissense: likely benign (0.0807); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2470637538 · 2 submitters · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## 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 2 submitters.

*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.Ile704Val |
| Coding change (HGVS c.) | c.2110A>G |
| MANE Select transcript | [NM_003151](https://www.ncbi.nlm.nih.gov/nuccore/NM_003151) |
| dbSNP | [rs2470637538](https://www.ncbi.nlm.nih.gov/snp/rs2470637538/) |
| Variant type | single nucleotide variant |
| Location | chr2:191031451-191031451 (GRCh38) |
| ClinVar | [VCV1960810](https://www.ncbi.nlm.nih.gov/clinvar/variation/1960810/) |

**All HGVS expressions:** `NC_000002.11:g.191896177T>C`, `NC_000002.12:g.191031451T>C`, `NG_012852.1:g.124749A>G`, `NG_012852.2:g.219724A>G`, `NM_001243835.2:c.2110A>G`, `NM_003151.4:c.2110A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0807)
- REVEL 0.272 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.826 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.896, GERP 1.87, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.34**. 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 0.47** across the covering region of the MANE Select transcript (191,029,843–191,031,485), spanning 1,642 bp. Chi-square p 1.5e-05. 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 **0.31**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.30** (loss), gain 0.05 / loss 0.30. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,182 in the highest group · 1/1,612,004 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-06-09.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-25 |

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

## Similar variants {#similar}

Related STAT4 variant pages (same residue, condition, or type): [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), [STAT4 p.Gly393Ala](/variant/stat4-p-gly393ala).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1960810). 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.*