# NM_005214.5(CTLA4):c.406C>T (p.Pro136Ser)

https://sugi.bio/variant/ctla4-p-pro136ser

## Summary

**CTLA4 p.Pro136Ser (c.406C>T)** is classified **Likely pathogenic** in CTLA4 (ClinVar, Expert panel, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9409); Absent from gnomAD v4.1; Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

**At a glance:** Likely pathogenic · review: Expert panel · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTLA4 gene that is considered likely 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.Pro136Ser |
| Coding change (HGVS c.) | c.406C>T |
| MANE Select transcript | [NM_005214](https://www.ncbi.nlm.nih.gov/nuccore/NM_005214) |
| Variant type | single nucleotide variant |
| Location | chr2:203870882-203870882 (GRCh38) |
| ClinVar | [VCV4683129](https://www.ncbi.nlm.nih.gov/clinvar/variation/4683129/) |

**All HGVS expressions:** `LRG_1220:g.8097C>T`, `LRG_1220t1:c.406C>T`, `NC_000002.11:g.204735605C>T`, `NC_000002.12:g.203870882C>T`, `NG_011502.1:g.8097C>T`, `NM_001037631.3:c.406C>T`, `NM_005214.5:c.406C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9409) — concordant with the pathogenic call
- REVEL 0.49 (indeterminate)
- SaProt LLR -9.458 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.71, GERP 1.5, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in CTLA4 (of 1,303 modeled).
- CADD: **PHRED 24.9**. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **136** lies in a β-strand; the ig-like v-type domain; the 'important for interaction with cd80 and cd86' region.

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.Pro136Ser 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 pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-11-24.

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

**ClinGen expert panel:** Likely Pathogenic — Antibody Deficiencies VCEP (autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS4_Supporting`, `PM1`, `PP1`, `PP4`, `PM5`.
*Considered but not met:* `PP3`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_005214.5(CTLA4):c.406C>T (p.Pro136Ser)is a missense variant encoding the replacement of proline with serine at amino acid 136. This variant is located within the MYPPPY functional domain (residues 134-139), which is required for interaction with CD80 and CD86 (PM1, PMID: 31396201). Another missense variant in the same codon, NM_005214.5(CTLA4):c.406C>G (p.Pro136Ala), has a lower Grantham score (27) than the variant under investigation (74) and has been classified as likely pathogenic for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency by the ClinGen Antibody Deficiencies VCEP (PM5, PMID: 27379089, PMID: 29729943). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with a phenotype that includes autoimmune cytopenias (2 pts), recurrent parotitis (4 pts), autoimmune gastrointestinal findings (4 pts), hepatosplenomegaly (2 pts), and recurrent viral infections (2 pts), with genotyping based on exome sequencing to exclude an alternative basis of disease in other loci such as LRBA, which together is highly specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (14 pts, PMID: 32009323, PP4). This variant has been reported in at least one other apparently unrelated patient reaching at least 10 phenotypic points, with a phenotype that includes recurrent upper and lower respiratory tract infections (4 pts), enteropathy and diarrhea (4 pts), T cell infiltration of the lung and gut (1 pt), autoimmune thrombocytopenia and autoimmune hemolytic anemia (2 pts), severe viral infection including skin findings (2 pts), recurrent fungal infections (1 pt), splenomegaly and lymphoproliferative disorder (2 pts), decreased circulating IgG level (2 pts), and post-vaccination measles (1 pt), without genotyping to exclude an alternative basis for disease in other loci (19 pts, PMID: 29729943, PS4_Supporting). The variant has been reported to segregate with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency through at least 1 affected meiosis from 1 family, with the affected status of the second family member confirmed to include hypogammaglobulinemia (2 pts), markedly decreased B-cells (1 pt), multiple episodes of illness including anemia and/or thrombocytopenia, abnormal lymphocyte subsets (1 pt), viral infection (2 pts), and malignancies (PMID: 32009323, PP1). The computational predictor REVEL gives a score of 0.490, which is below the ClinGen Antibody Deficiencies VCEP threshold of >0.75 and does not predict a damaging effect. The computational predictor CADD gives a PHRED score of 24.9, which is above the ClinGen Antibody Deficiencies VCEP threshold of >20 and predicts a damaging effect on CTLA4 function. Because the two predictors do not agree, PP3 is not met. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02 for donor gain, which is below the ClinGen Antibody Deficiencies VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: PM1, PM5, PM2_Supporting, PS4_Supporting, PP1, and PP4. (VCEP specifications version 2.0.0).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50095 · approved 2026-09-14 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/7031aeab-5c4c-497a-a1bd-d026b0aa03fa).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ClinGen Primary Immune Regulatory Disorders Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-11-24 |

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

## Same-residue context {#hotspot}

Residue **136** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CTLA4 p.Pro136Leu](/variant/ctla4-p-pro136leu), [CTLA4 p.Pro136Ala](/variant/ctla4-p-pro136ala). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CTLA4 variant pages (same residue, condition, or type): [CTLA4 p.Pro136Ala](/variant/ctla4-p-pro136ala), [CTLA4 p.Pro136Leu](/variant/ctla4-p-pro136leu), [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.Pro137Arg](/variant/ctla4-p-pro137arg), [CTLA4 p.Pro137Leu](/variant/ctla4-p-pro137leu).

### 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 4683129). 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.*