# NM_139321.3(ATRN):c.1661G>C (p.Arg554Pro)

https://sugi.bio/variant/atrn-p-arg554pro

## Summary

**ATRN p.Arg554Pro (c.1661G>C)** is classified **Uncertain significance** in ATRN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.9971); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the ATRN 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 | [ATRN](https://sugi.bio/atlas/gene/ATRN/) |
| Protein change (HGVS p.) | p.Arg554Pro |
| Coding change (HGVS c.) | c.1661G>C |
| MANE Select transcript | [NM_139321](https://www.ncbi.nlm.nih.gov/nuccore/NM_139321) |
| Variant type | single nucleotide variant |
| Location | chr20:3563238-3563238 (GRCh38) |
| ClinVar | [VCV3332537](https://www.ncbi.nlm.nih.gov/clinvar/variation/3332537/) |

**All HGVS expressions:** `NC_000020.10:g.3543885G>C`, `NC_000020.11:g.3563238G>C`, `NG_029406.1:g.97221G>C`, `NM_001207047.3:c.1313G>C`, `NM_001323332.2:c.1661G>C`, `NM_139321.3:c.1661G>C`, `NM_139322.4:c.1661G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9971)
- REVEL 0.887 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.872 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.36) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.801, GERP 1.94, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in ATRN (of 8,415 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 0.89** across the covering region of the MANE Select transcript (3,471,108–3,576,905), spanning 105,797 bp. Chi-square p 0.00041. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.36**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.36**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**.
- Pangolin: Δ**0.44** (gain), gain 0.44 / loss 0.34. SpliceAI calls loss. 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 **8.48e-05%** (nfe) · 1/1,179,244 in the highest group · 1/1,460,340 alleles overall — very rare (popmax 8.48e-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}

**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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-12.

**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 | 2024-05-12 |

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

## 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 3332537). 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.*