# NM_001393586.1(MYO7B):c.5900C>T (p.Ala1967Val)

https://sugi.bio/variant/myo7b-p-ala1967val

## Summary

**MYO7B p.Ala1967Val (c.5900C>T)** is classified **Uncertain significance** in MYO7B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.0808); Ultra-rare (popmax 0.0322%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs199543587 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0322%, afr)

## For patients & families {#patients}

This is a change in the MYO7B 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 | [MYO7B](https://sugi.bio/atlas/gene/MYO7B/) |
| Protein change (HGVS p.) | p.Ala1967Val |
| Coding change (HGVS c.) | c.5900C>T |
| MANE Select transcript | [NM_001393586](https://www.ncbi.nlm.nih.gov/nuccore/NM_001393586) |
| dbSNP | [rs199543587](https://www.ncbi.nlm.nih.gov/snp/rs199543587/) |
| Variant type | single nucleotide variant |
| Location | chr2:127635801-127635801 (GRCh38) |
| ClinVar | [VCV2372753](https://www.ncbi.nlm.nih.gov/clinvar/variation/2372753/) |

**All HGVS expressions:** `NC_000002.11:g.128393376C>T`, `NC_000002.12:g.127635801C>T`, `NG_052848.1:g.105113C>T`, `NG_096555.1:g.49C>T`, `NM_001080527.2:c.5822C>T`, `NM_001393586.1:c.5900C>T`, `NM_001393594.1:c.2381C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0808)
- REVEL 0.176 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.227 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.589, GERP -1.81, phastCons 0.126 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A1941V** vs ClinVar **A1967V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 17.47**. 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 1.07** across the covering region of the MANE Select transcript (127,629,673–127,637,414), spanning 7,741 bp. Chi-square p 0.063. 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 **0.00**, acceptor gain **0.01**, donor gain **0.20**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.20**.
- Population frequency (gnomAD v4.1): grpmax **0.0322%** (afr) · FAF95 0.0221% · FAF99 0.0188% · 24/74,534 in the highest group · 36/1,594,598 alleles overall — ultra-rare (popmax 0.0322%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0322% | 3,106 |
| Remaining individuals (not grpmax-eligible) | 0.0113% | 8,833 |
| South Asian | 0.00228% | 43,824 |
| European (non-Finnish) | 0.000256% | 390,271 |

*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}

**MYO7B** population constraint: LOEUF 0.956, pLI 2.9795e-58, missense-Z 0.49486. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **1941** lies in the ferm 2 domain; the 'mediates interaction with cdhr2, cdhr5 and ush1c' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 78.34, 19% of residues very-high.

**3 experimental structure(s)** (PDB): [5MV7](https://www.rcsb.org/structure/5MV7), [5MV8](https://www.rcsb.org/structure/5MV8), [5XBF](https://www.rcsb.org/structure/5XBF).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-10.

**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 | 2024-12-10 |

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

## Similar variants {#similar}

Related MYO7B variant pages (same residue, condition, or type): [MYO7B p.Thr349Met](/variant/myo7b-p-thr349met), [MYO7B p.Ile1309Val](/variant/myo7b-p-ile1309val), [MYO7B p.Val1556Ile](/variant/myo7b-p-val1556ile), [MYO7B p.Val1876=](/variant/myo7b-p-val1876), [MYO7B p.Ala1010Thr](/variant/myo7b-p-ala1010thr), [MYO7B p.Ala1092Thr](/variant/myo7b-p-ala1092thr), [MYO7B p.Ala1109Thr](/variant/myo7b-p-ala1109thr), [MYO7B p.Ala1126Thr](/variant/myo7b-p-ala1126thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2372753). 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.*