# NM_005214.5(CTLA4):c.219G>C (p.Val73=)

https://sugi.bio/variant/ctla4-p-val73

## Summary

**CTLA4 p.Val73= (c.219G>C)** is classified **Likely benign** in CTLA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-19). Very rare (popmax 0.000424%, nfe); Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs866679318 · 1 submitter · 1 linked condition · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the CTLA4 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Val73= |
| Coding change (HGVS c.) | c.219G>C |
| MANE Select transcript | [NM_005214](https://www.ncbi.nlm.nih.gov/nuccore/NM_005214) |
| dbSNP | [rs866679318](https://www.ncbi.nlm.nih.gov/snp/rs866679318/) |
| Variant type | single nucleotide variant |
| Location | chr2:203870695-203870695 (GRCh38) |
| ClinVar | [VCV1613419](https://www.ncbi.nlm.nih.gov/clinvar/variation/1613419/) |

**All HGVS expressions:** `LRG_1220:g.7910G>C`, `LRG_1220t1:c.219G>C`, `NC_000002.11:g.204735418G>C`, `NC_000002.12:g.203870695G>C`, `NG_011502.1:g.7910G>C`, `NM_001037631.3:c.219G>C`, `NM_005214.5:c.219G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.928, GERP -1.8, phastCons 1 — weakly conserved position
- CADD: **PHRED 6.974**. 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.*
- 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,180,052 in the highest group · 5/1,614,118 alleles overall — very rare (popmax 0.000424%, 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}

**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 **73** 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.Val73= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-19 |

## 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, CTLA4 HAPLOINSUFFICIENCY WITH AUTOIMMUNE INFILTRATION, Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency, Autoimmune lymphoproliferative syndrome type V, IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION, Autoimmune lymphoproliferative syndrome 5.

## Same-residue context {#hotspot}

Residue **73** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CTLA4 p.Val73fs](/variant/ctla4-p-val73fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CTLA4 variant pages (same residue, condition, or type): [CTLA4 p.Val73fs](/variant/ctla4-p-val73fs), [CTLA4 p.Arg51Ter](/variant/ctla4-p-arg51ter), [CTLA4 p.Arg75Trp](/variant/ctla4-p-arg75trp), [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 1613419). 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.*