# NM_001142725.2(ERI2):c.5C>T (p.Ala2Val)

https://sugi.bio/variant/eri2-p-ala2val

## Summary

**ERI2 p.Ala2Val (c.5C>T)** is classified **Uncertain significance** in ERI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). AlphaMissense: likely pathogenic (0.8834); Very rare (popmax 8.71e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2543414902 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.71e-05%, nfe)

## For patients & families {#patients}

This is a change in the ERI2 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 | [ERI2](https://sugi.bio/atlas/gene/ERI2/) |
| Protein change (HGVS p.) | p.Ala2Val |
| Coding change (HGVS c.) | c.5C>T |
| MANE Select transcript | [NM_001142725](https://www.ncbi.nlm.nih.gov/nuccore/NM_001142725) |
| dbSNP | [rs2543414902](https://www.ncbi.nlm.nih.gov/snp/rs2543414902/) |
| Variant type | single nucleotide variant |
| Location | chr16:20806426-20806426 (GRCh38) |
| ClinVar | [VCV2277572](https://www.ncbi.nlm.nih.gov/clinvar/variation/2277572/) |

**All HGVS expressions:** `NC_000016.10:g.20806426G>A`, `NC_000016.9:g.20817748G>A`, `NG_133346.1:g.859G>A`, `NM_001142725.2:c.5C>T`, `NM_080663.3:c.5C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8834)
- REVEL 0.134 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -2.99 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- SpliceAI predicts **donor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.93, GERP 1.76, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in ERI2 (of 4,049 modeled).
- CADD: **PHRED 27.1**. 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 0.87** across the covering region of the MANE Select transcript (20,797,727–20,806,430), spanning 8,703 bp. Chi-square p 0.00034. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.27**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**.
- Population frequency (gnomAD v4.1): grpmax **8.71e-05%** (nfe) · 1/1,148,072 in the highest group · 1/1,400,642 alleles overall — very rare (popmax 8.71e-05%, nfe).

*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}

**ERI2** population constraint: LOEUF 0.981, pLI 5.1804e-10, missense-Z 1.7558. *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 59.66, 31% of residues very-high.

**2 experimental structure(s)** (PDB): [7N8V](https://www.rcsb.org/structure/7N8V), [7N8W](https://www.rcsb.org/structure/7N8W).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-17.

**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 | 2022-02-17 |

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

## Similar variants {#similar}

Related ERI2 variant pages (same residue, condition, or type): [ACSM3 p.Asn444His](/variant/acsm3-p-asn444his), [ACSM3 p.Gly260Ala](/variant/acsm3-p-gly260ala), [ACSM3 p.Pro268Arg](/variant/acsm3-p-pro268arg), [ACSM3 p.Trp273Arg](/variant/acsm3-p-trp273arg), [ACSM3 p.Tyr457Cys](/variant/acsm3-p-tyr457cys), [ERI2 p.Ala102Ser](/variant/eri2-p-ala102ser), [ERI2 p.Ala19Val](/variant/eri2-p-ala19val), [ERI2 p.Ala200Val](/variant/eri2-p-ala200val).

### 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 2277572). 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.*