# NM_005214.5(CTLA4):c.370A>C (p.Thr124Pro)

https://sugi.bio/variant/ctla4-p-thr124pro

## Summary

**CTLA4 p.Thr124Pro (c.370A>C)** is classified **Uncertain significance** in CTLA4 (ClinVar, Expert panel, 2 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.3431); Absent from gnomAD v4.1; Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs1286462906 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## 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.Thr124Pro |
| Coding change (HGVS c.) | c.370A>C |
| MANE Select transcript | [NM_005214](https://www.ncbi.nlm.nih.gov/nuccore/NM_005214) |
| dbSNP | [rs1286462906](https://www.ncbi.nlm.nih.gov/snp/rs1286462906/) |
| Variant type | single nucleotide variant |
| Location | chr2:203870846-203870846 (GRCh38) |
| ClinVar | [VCV2203245](https://www.ncbi.nlm.nih.gov/clinvar/variation/2203245/) |

**All HGVS expressions:** `LRG_1220:g.8061A>C`, `LRG_1220t1:c.370A>C`, `NC_000002.11:g.204735569A>C`, `NC_000002.12:g.203870846A>C`, `NG_011502.1:g.8061A>C`, `NM_001037631.3:c.370A>C`, `NM_005214.5:c.370A>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3431) — no call either way
- REVEL 0.812 (moderately pathogenic-leaning)
- SaProt LLR -15.44 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 6.089, GERP -0.977, phastCons 1 — highly conserved
- CADD: **PHRED 23.4**. 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: **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 **124** lies in a disulfide bond; 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.Thr124Pro 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 Expert panel *(reviewed by expert panel)*, last evaluated 2025-11-24.

**Submitter consensus:** conflicting (1 Uncertain Significance, 1 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

**ClinGen expert panel:** Uncertain Significance — Antibody Deficiencies VCEP (autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS4_Supporting`, `PS3_Supporting`, `PP3`.
*Considered but not met:* `PP1`, `PP4`, `PM5`, `BP4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_005214.5(CTLA4):c.370A>C (p.Thr124Pro) is a missense variant replacing threonine with proline at amino acid 124. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 1 proband meeting the VCEP standard for phenotypic criteria, with a phenotype that includes splenomegaly and lymphadenopathy (2 pts), autoimmune hemolytic anemia (2 pts), autoimmune thyroiditis (1 pt), hypogammaglobulinemia (2 pts), granulomatous lymphocytic interstitial lung disease (4 pts), and organ infiltration of the bone marrow, kidney, brain, and liver (1 pt), without genotyping that excluded causes in other loci (12 total points, PMID: 25329329, PMID: 34111452, PMID: 27418640, PS4_Supporting). The computational predictor REVEL gives a score of 0.812 (which is above the threshold of 0.75) and the computational predictor CADD gives a score of 24.7 (which is above the threshold of 20) (PP3). The splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen Antibody Deficiencies VCEP recommended threshold of >0.2 and does not predict an impact on CTLA4 splicing. A soluble CD80 ligand uptake assay performed in CHO cells expressing either wild-type or mutant CTLA4 showed that the percentage of CD80-Ig-posititve cells was 5.99% in mutated cells (PMID: 25329329).The percentage of CD80-Ig-posititve cells in wild type cells was 55.4%. These results indicate that this variant impacts protein function by impairing the cells' ability to take up soluble CD80-immunoglobulin fusion protein (PMID: 25329329, PS3_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: PS3_Supporting, PS4_Supporting, PM2_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 09/18/2025).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50095 · approved 2025-11-24 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c50ebd08-d4de-4d57-a511-d156aa6c6f67).*
*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 | Uncertain Significance | reviewed by expert panel | curation | 2025-11-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-02 |

## 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, Autoimmune lymphoproliferative syndrome 5, IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION.

## Similar variants {#similar}

Related CTLA4 variant pages (same residue, condition, or type): [CTLA4 p.Thr124Met](/variant/ctla4-p-thr124met), [CTLA4 p.Thr124=](/variant/ctla4-p-thr124), [CTLA4 p.Thr124Ser](/variant/ctla4-p-thr124ser), [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).

### 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 2203245). 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.*