# NM_030893.4(CD1E):c.1030C>T (p.Pro344Ser)

https://sugi.bio/variant/cd1e-p-pro344ser

## Summary

**CD1E p.Pro344Ser (c.1030C>T)** is classified **Uncertain significance** in CD1E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0272%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs200792123 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0272%, nfe)

## For patients & families {#patients}

This is a change in the CD1E 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 | [CD1E](https://sugi.bio/atlas/gene/CD1E/) |
| Protein change (HGVS p.) | p.Pro344Ser |
| Coding change (HGVS c.) | c.1030C>T |
| MANE Select transcript | [NM_030893](https://www.ncbi.nlm.nih.gov/nuccore/NM_030893) |
| dbSNP | [rs200792123](https://www.ncbi.nlm.nih.gov/snp/rs200792123/) |
| Variant type | single nucleotide variant |
| Location | chr1:158356759-158356759 (GRCh38) |
| ClinVar | [VCV2596242](https://www.ncbi.nlm.nih.gov/clinvar/variation/2596242/) |

**All HGVS expressions:** `NC_000001.10:g.158326549C>T`, `NC_000001.11:g.158356759C>T`, `NM_001042583.3:c.999-5C>T`, `NM_001042584.3:c.*53C>T`, `NM_001042585.3:c.834-5C>T`, `NM_001042586.3:c.432-5C>T`, `NM_001042587.3:c.*53C>T`, `NM_001185107.2:c.760C>T`, `NM_001185108.2:c.564-5C>T`, `NM_001185110.2:c.267-5C>T`, `NM_001185112.2:c.463C>T`, `NM_001185113.2:c.298C>T`, `NM_001185114.2:c.733C>T`, `NM_001185115.2:c.729-5C>T`, `NM_030893.4:c.1030C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.07)
- REVEL 0.006 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.726 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.39, GERP -3.53 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.482**. 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 1.04** across the covering region of the MANE Select transcript (158,353,989–158,356,893), spanning 2,904 bp. Chi-square p 0.34. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.91 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0272%** (nfe) · FAF95 0.0247% · FAF99 0.0238% · 321/1,179,938 in the highest group · 336/1,613,752 alleles overall — ultra-rare (popmax 0.0272%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0272% | 3,676 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,942 |
| African / African-American | 0.00535% | 18,709 |
| Admixed American | 0.00334% | 29,980 |

*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}

**CD1E** population constraint: LOEUF 1.517, pLI 1.3883e-21, missense-Z 0.024213. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.66, 66% of residues very-high.

**1 experimental structure(s)** (PDB): [3S6C](https://www.rcsb.org/structure/3S6C).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-24.

**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 | 2025-10-24 |

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

## Similar variants {#similar}

Related CD1E variant pages (same residue, condition, or type): [CD1E p.Asp264=](/variant/cd1e-p-asp264), [CD1E p.His102Arg](/variant/cd1e-p-his102arg), [CD1E p.Ala110Val](/variant/cd1e-p-ala110val), [CD1E p.Ala127Thr](/variant/cd1e-p-ala127thr), [CD1E p.Ala195Val](/variant/cd1e-p-ala195val), [CD1E p.Arg164Trp](/variant/cd1e-p-arg164trp), [CD1E p.Arg192Gln](/variant/cd1e-p-arg192gln), [CD1E p.Arg207Trp](/variant/cd1e-p-arg207trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2596242). 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.*