# NM_005214.5(CTLA4):c.224G>A (p.Arg75Gln)

https://sugi.bio/variant/ctla4-p-arg75gln

## Summary

**CTLA4 p.Arg75Gln (c.224G>A)** is classified **Uncertain significance** in CTLA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.0011%, nfe); Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1196646336 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, nfe)

## For patients & families {#patients}

This is a change in the CTLA4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CTLA4 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased circulating antibody level — Very frequent (99-80%)
- Atopic dermatitis — Frequent (79-30%)
- Splenomegaly — Frequent (79-30%)
- Autoimmune hemolytic anemia — Frequent (79-30%)
- Autoimmune thrombocytopenia — Frequent (79-30%)
- Diarrhea — Frequent (79-30%)
- Pneumonia — Frequent (79-30%)
- Hepatomegaly — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012316/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTLA4](https://sugi.bio/atlas/gene/CTLA4/) |
| Protein change (HGVS p.) | p.Arg75Gln |
| Coding change (HGVS c.) | c.224G>A |
| MANE Select transcript | [NM_005214](https://www.ncbi.nlm.nih.gov/nuccore/NM_005214) |
| dbSNP | [rs1196646336](https://www.ncbi.nlm.nih.gov/snp/rs1196646336/) |
| Variant type | single nucleotide variant |
| Location | chr2:203870700-203870700 (GRCh38) |
| ClinVar | [VCV943305](https://www.ncbi.nlm.nih.gov/clinvar/variation/943305/) |

**All HGVS expressions:** `LRG_1220:g.7915G>A`, `LRG_1220t1:c.224G>A`, `NC_000002.11:g.204735423G>A`, `NC_000002.12:g.203870700G>A`, `NG_011502.1:g.7915G>A`, `NM_001037631.3:c.224G>A`, `NM_005214.5:c.224G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1185)
- REVEL 0.285 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.079 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 8.689, GERP 1.44, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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 0.66** across the covering region of the MANE Select transcript (203,870,611–203,872,809), spanning 2,198 bp. Chi-square p 3.2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (nfe) · FAF95 0.000615% · FAF99 0.000474% · 13/1,180,032 in the highest group · 14/1,461,890 alleles overall — very rare (popmax 0.0011%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |
| European (non-Finnish) (grpmax) | 0.0011% | 90,771 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*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}

**CTLA4** population constraint: LOEUF 0.211, pLI 0.99829, missense-Z 2.0899. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency** — Definitive (AD)

## Protein context {#protein}

Residue **75** lies in a disulfide bond; a β-strand; the ig-like v-type domain.

AlphaFold model confidence (whole protein): pLDDT 79.67, 48% of residues very-high.

**22 experimental structure(s)** (PDB): [1AH1](https://www.rcsb.org/structure/1AH1), [1H6E](https://www.rcsb.org/structure/1H6E), [1I85](https://www.rcsb.org/structure/1I85), [1I8L](https://www.rcsb.org/structure/1I8L), [2X44](https://www.rcsb.org/structure/2X44), [3BX7](https://www.rcsb.org/structure/3BX7) — incl. mutant structure 7SU0.

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

*Describes the biological roles of CTLA4 (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:** CTLA4's established molecular role includes receptor decoy activity. p.Arg75Gln falls in the ig-like v-type domain.


### Pathways affected {#pathways}

CTLA4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | curated |
| [Co-stimulation by CD28](https://reactome.org/content/detail/R-HSA-389356) | curated |
| [RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)](https://reactome.org/content/detail/R-HSA-8877330) | curated |

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

**Molecular function:** receptor decoy activity.

**Biological process:** DNA damage response, negative regulation of B cell proliferation, positive regulation of apoptotic process, negative regulation of regulatory T cell differentiation, B cell receptor signaling pathway, negative regulation of T cell receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-29.

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

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-29 |

## Associated conditions {#conditions}

[autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency](https://sugi.bio/atlas/disease/autoimmune-lymphoproliferative-syndrome-due-to-ctla4-haploinsufficiency/).

**Reported phenotype names (ClinVar):** Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, not provided, none provided, Autoimmune lymphoproliferative syndrome type V, Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency, Autoimmune lymphoproliferative syndrome 5, CTLA4 HAPLOINSUFFICIENCY WITH AUTOIMMUNE INFILTRATION, IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION.

## Same-residue context {#hotspot}

Residue **75** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CTLA4 p.Arg75Trp](/variant/ctla4-p-arg75trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CTLA4 variant pages (same residue, condition, or type): [CTLA4 p.Arg75Trp](/variant/ctla4-p-arg75trp), [CTLA4 p.Arg75=](/variant/ctla4-p-arg75), [CTLA4 p.Arg51Ter](/variant/ctla4-p-arg51ter), [CTLA4 p.Asp153Asn](/variant/ctla4-p-asp153asn), [CTLA4 p.Cys35Ter](/variant/ctla4-p-cys35ter), [CTLA4 p.Pro136Ala](/variant/ctla4-p-pro136ala), [CTLA4 p.Pro136Leu](/variant/ctla4-p-pro136leu), [CTLA4 p.Pro136Ser](/variant/ctla4-p-pro136ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 943305). 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.*