# NM_001127392.3(MYRF):c.3207C>T (p.Pro1069=)

https://sugi.bio/variant/myrf-p-pro1069

## Summary

**MYRF p.Pro1069= (c.3207C>T)** is classified **Benign** in MYRF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). Low-frequency (popmax 3.5%, sas).

**At a glance:** Benign · review: Multiple submitters · rsID rs370887875 · 3 submitters · low-frequency (popmax 3.5%, sas)

## For patients & families {#patients}

This is a change in the MYRF gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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 | [MYRF](https://sugi.bio/atlas/gene/MYRF/) |
| Protein change (HGVS p.) | p.Pro1069= |
| Coding change (HGVS c.) | c.3207C>T |
| MANE Select transcript | [NM_001127392](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127392) |
| dbSNP | [rs370887875](https://www.ncbi.nlm.nih.gov/snp/rs370887875/) |
| Variant type | single nucleotide variant |
| Location | chr11:61784292-61784292 (GRCh38) |
| ClinVar | [VCV722194](https://www.ncbi.nlm.nih.gov/clinvar/variation/722194/) |

**All HGVS expressions:** `NC_000011.10:g.61784292C>T`, `NC_000011.9:g.61551764C>T`, `NG_047038.1:g.36656C>T`, `NM_001127392.3:c.3207C>T`, `NM_013279.4:c.3087C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -8.003, GERP -3.81 — fast-evolving / accelerated position
- CADD: **PHRED 8.004**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **3.5%** (sas) · FAF95 3.4% · FAF99 3.36% · 3,189/91,040 in the highest group · 3,443/1,613,882 alleles overall — low-frequency (popmax 3.5%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 3.5% | 29 |
| Remaining individuals (not grpmax-eligible) | 0.238% | 419 |
| Middle Eastern | 0.148% | 674 |
| Admixed American | 0.00833% | 12,002 |
| European (non-Finnish) | 0.00729% | 13,721 |
| African / African-American | 0.00667% | 14,999 |

*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}

**MYRF** population constraint: LOEUF 0.215, pLI 1, missense-Z 3.5595. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **cardiac-urogenital syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **1069** lies in a UniProt-annotated variant site (in cugs; likely pathogenic); a UniProt-annotated variant site (in nno1; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 61.76, 29% of residues very-high.

**2 experimental structure(s)** (PDB): [5YHU](https://www.rcsb.org/structure/5YHU), [5ZHU](https://www.rcsb.org/structure/5ZHU).

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-12-31.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-02-22 |

**Reported phenotype names (ClinVar):** not provided, MYRF-related disorder, none provided, MYRF-related condition, MYRF-related disorders.

## Similar variants {#similar}

Related MYRF variant pages (same residue, condition, or type): [MYRF p.Gln150Ter](/variant/myrf-p-gln150ter), [MYRF p.Trp939Ter](/variant/myrf-p-trp939ter), [MYRF p.Ala1001Ser](/variant/myrf-p-ala1001ser), [MYRF p.Arg174Cys](/variant/myrf-p-arg174cys), [MYRF p.Arg733Gln](/variant/myrf-p-arg733gln), [MYRF p.Asn267Ser](/variant/myrf-p-asn267ser), [MYRF p.Glu421Lys](/variant/myrf-p-glu421lys), [MYRF p.Pro743Ser](/variant/myrf-p-pro743ser).

### 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 722194). 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.*