# NM_016382.4(CD244):c.455G>T (p.Cys152Phe)

https://sugi.bio/variant/cd244-p-cys152phe

## Summary

**CD244 p.Cys152Phe (c.455G>T)** is classified **Uncertain significance** in CD244 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely pathogenic (0.9416); Very rare (popmax 0.00212%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00212%, nfe)

## For patients & families {#patients}

This is a change in the CD244 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CD244](https://sugi.bio/atlas/gene/CD244/) |
| Protein change (HGVS p.) | p.Cys152Phe |
| Coding change (HGVS c.) | c.455G>T |
| MANE Select transcript | [NM_016382](https://www.ncbi.nlm.nih.gov/nuccore/NM_016382) |
| Variant type | single nucleotide variant |
| Location | chr1:160841410-160841410 (GRCh38) |
| ClinVar | [VCV3829462](https://www.ncbi.nlm.nih.gov/clinvar/variation/3829462/) |

**All HGVS expressions:** `NC_000001.10:g.160811200C>A`, `NC_000001.11:g.160841410C>A`, `NG_015991.1:g.26493G>T`, `NM_001166663.2:c.470G>T`, `NM_001166664.2:c.379+174G>T`, `NM_016382.4:c.455G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9416)
- REVEL 0.857 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.967 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.264, GERP 1.12, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **C157F** vs ClinVar **C152F**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in CD244 (of 2,164 modeled).
- CADD: **PHRED 29.8**. 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 0.95** across the covering region of the MANE Select transcript (160,831,350–160,862,677), spanning 31,327 bp. Chi-square p 0.33. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**.
- Pangolin: Δ**0.38** (gain), gain 0.38 / loss 0.00. 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 **0.00212%** (nfe) · FAF95 0.00145% · FAF99 0.00123% · 25/1,180,036 in the highest group · 26/1,461,862 alleles overall — very rare (popmax 0.00212%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00212% | 47,201 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,506 |

*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}

**CD244** population constraint: LOEUF 0.501, pLI 0.98103, missense-Z 0.69468. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **152** lies in the ig-like 2 domain.

AlphaFold model confidence (whole protein): pLDDT 71.23, 24% of residues very-high.

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

*Describes the biological roles of CD244 (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:** CD244's established molecular role includes signaling receptor activity. p.Cys152Phe falls in the ig-like 2 domain.


### Pathways affected {#pathways}

CD244 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |

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

**Molecular function:** signaling receptor activity, MHC class I protein binding.

**Biological process:** natural killer cell activation involved in immune response, natural killer cell activation, positive regulation of type II interferon production, positive regulation of interleukin-8 production, positive regulation of inositol phosphate biosynthetic process, positive regulation of granzyme B production.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-27 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD244 variant pages (same residue, condition, or type): [CD244 c.*578T>C](/variant/cd244-c-star-578t-c), [CD244 p.Ile229Val](/variant/cd244-p-ile229val), [CD244 p.Leu13=](/variant/cd244-p-leu13), [CD244 c.380-3C>T](/variant/cd244-c-380-minus-3c-t), [CD244 c.380-4C>T](/variant/cd244-c-380-minus-4c-t), [CD244 p.Ala234Ser](/variant/cd244-p-ala234ser), [CD244 p.Arg133Cys](/variant/cd244-p-arg133cys), [CD244 p.Arg355His](/variant/cd244-p-arg355his).

### 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 3829462). 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.*