# NM_015307.2(ENTREP2):c.1253C>G (p.Ser418Trp)

https://sugi.bio/variant/entrep2-p-ser418trp

## Summary

**ENTREP2 p.Ser418Trp (c.1253C>G)** is classified **Uncertain significance** in ENTREP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1218); Ultra-rare (popmax 0.0262%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0262%, sas)

## For patients & families {#patients}

This is a change in the ENTREP2 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 | [ENTREP2](https://sugi.bio/atlas/gene/ENTREP2/) |
| Protein change (HGVS p.) | p.Ser418Trp |
| Coding change (HGVS c.) | c.1253C>G |
| MANE Select transcript | [NM_015307](https://www.ncbi.nlm.nih.gov/nuccore/NM_015307) |
| Variant type | single nucleotide variant |
| Location | chr15:29124737-29124737 (GRCh38) |
| ClinVar | [VCV3275579](https://www.ncbi.nlm.nih.gov/clinvar/variation/3275579/) |

**All HGVS expressions:** `NC_000015.10:g.29124737G>C`, `NC_000015.9:g.29416940G>C`, `NM_001387214.1:c.1118C>G`, `NM_001387215.1:c.965C>G`, `NM_001387216.1:c.965C>G`, `NM_001387217.1:c.830C>G`, `NM_015307.2:c.1253C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1218)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.088 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.099, GERP -2.44 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 16.07**. 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 (29,123,342–29,570,723), spanning 447,381 bp. Chi-square p 0.2. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.14**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 50 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0262%** (sas) · FAF95 0.0177% · FAF99 0.0149% · 22/84,062 in the highest group · 41/1,550,652 alleles overall — ultra-rare (popmax 0.0262%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0262% | 3,821 |
| Remaining individuals (not grpmax-eligible) | 0.00499% | 20,034 |
| European (non-Finnish) | 0.00139% | 71,686 |

*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.*

## Protein context {#protein}

Residue **418** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.09, 9% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-20.

**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 | 2024-05-20 |

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

## Similar variants {#similar}

Related ENTREP2 variant pages (same residue, condition, or type): [ENTREP2 p.Gly126Ser](/variant/entrep2-p-gly126ser), [NSMCE3 p.Ala293Thr](/variant/nsmce3-p-ala293thr), [NSMCE3 p.Arg133Ser](/variant/nsmce3-p-arg133ser), [NSMCE3 p.Gln14His](/variant/nsmce3-p-gln14his), [NSMCE3 p.Glu45Gln](/variant/nsmce3-p-glu45gln), [NSMCE3 p.Gly78Arg](/variant/nsmce3-p-gly78arg), [NSMCE3 p.Ile193Val](/variant/nsmce3-p-ile193val), [NSMCE3 p.Pro65Leu](/variant/nsmce3-p-pro65leu).

### 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 3275579). 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.*