# NM_139321.3(ATRN):c.1044C>T (p.Val348=)

https://sugi.bio/variant/atrn-p-val348

## Summary

**ATRN p.Val348= (c.1044C>T)** is classified **Likely benign** in ATRN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-21). Ultra-rare (popmax 0.0626%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs756629370 · 1 submitter · ultra-rare (popmax 0.0626%, amr)

## For patients & families {#patients}

This is a change in the ATRN gene that is classified as likely benign — not considered disease-causing, 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 | [ATRN](https://sugi.bio/atlas/gene/ATRN/) |
| Protein change (HGVS p.) | p.Val348= |
| Coding change (HGVS c.) | c.1044C>T |
| MANE Select transcript | [NM_139321](https://www.ncbi.nlm.nih.gov/nuccore/NM_139321) |
| dbSNP | [rs756629370](https://www.ncbi.nlm.nih.gov/snp/rs756629370/) |
| Variant type | single nucleotide variant |
| Location | chr20:3549270-3549270 (GRCh38) |
| ClinVar | [VCV2054841](https://www.ncbi.nlm.nih.gov/clinvar/variation/2054841/) |

**All HGVS expressions:** `NC_000020.10:g.3529917C>T`, `NC_000020.11:g.3549270C>T`, `NG_029406.1:g.83253C>T`, `NM_001207047.3:c.696C>T`, `NM_001323332.2:c.1044C>T`, `NM_139321.3:c.1044C>T`, `NM_139322.4:c.1044C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.193, GERP -0.381, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.353**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.35 donor 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 **0.0626%** (amr) · FAF95 0.0466% · FAF99 0.0411% · 37/59,080 in the highest group · 38/1,609,868 alleles overall — ultra-rare (popmax 0.0626%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0626% | 1,597 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,336 |

*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}

**ATRN** population constraint: LOEUF 0.395, pLI 1, missense-Z 2.9594. *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 79.27, 31% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-21.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-21 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ATRN variant pages (same residue, condition, or type): [ATRN p.Ala438Gly](/variant/atrn-p-ala438gly), [ATRN p.Ala87Val](/variant/atrn-p-ala87val), [ATRN p.Arg1417Gln](/variant/atrn-p-arg1417gln), [ATRN p.Arg173His](/variant/atrn-p-arg173his), [ATRN p.Asn1035Ser](/variant/atrn-p-asn1035ser), [ATRN p.Asn213Ser](/variant/atrn-p-asn213ser), [ATRN p.Asn300Thr](/variant/atrn-p-asn300thr), [ATRN p.Asp508Asn](/variant/atrn-p-asp508asn).

### 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 2054841). 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.*