# NM_022369.4(STRA6):c.357C>T (p.Pro119=)

https://sugi.bio/variant/stra6-p-pro119

## Summary

**STRA6 p.Pro119= (c.357C>T)** is classified **Conflicting classifications of pathogenicity** in STRA6 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-01). Rare (popmax 0.17%, nfe); Associated with microphthalmia, syndromic 9.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139775570 · 7 submitters · 1 linked condition · rare (popmax 0.17%, nfe)

## For patients & families {#patients}

This is a change in the STRA6 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to microphthalmia, syndromic 9.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000713/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STRA6](https://sugi.bio/atlas/gene/STRA6/) |
| Protein change (HGVS p.) | p.Pro119= |
| Coding change (HGVS c.) | c.357C>T |
| MANE Select transcript | [NM_022369](https://www.ncbi.nlm.nih.gov/nuccore/NM_022369) |
| dbSNP | [rs139775570](https://www.ncbi.nlm.nih.gov/snp/rs139775570/) |
| Variant type | single nucleotide variant |
| Location | chr15:74196057-74196057 (GRCh38) |
| ClinVar | [VCV287343](https://www.ncbi.nlm.nih.gov/clinvar/variation/287343/) |

**All HGVS expressions:** `NC_000015.10:g.74196057G>A`, `NC_000015.9:g.74488398G>A`, `NG_009207.1:g.17974C>T`, `NM_001142617.2:c.357C>T`, `NM_001142618.2:c.357C>T`, `NM_001142619.2:c.330C>T`, `NM_001142620.2:c.357C>T`, `NM_001199040.2:c.468C>T`, `NM_001199041.2:c.402C>T`, `NM_001199042.2:c.474C>T`, `NM_022369.4:c.357C>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 -4.608, GERP -4.57 — fast-evolving / accelerated position
- CADD: **PHRED 0.64**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, G>T, IS in the release and scores Δ0.53 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.17%** (nfe) · FAF95 0.164% · FAF99 0.162% · 2,009/1,180,016 in the highest group · 2,173/1,613,852 alleles overall — rare (popmax 0.17%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 3.51% | 29 |
| European (non-Finnish) (grpmax) | 0.17% | 587 |
| Finnish (not grpmax-eligible) | 0.075% | 1,333 |
| Remaining individuals (not grpmax-eligible) | 0.072% | 1,388 |
| African / African-American | 0.0414% | 2,415 |
| South Asian | 0.00549% | 18,212 |
| Admixed American | 0.005% | 19,995 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**STRA6** population constraint: LOEUF 0.725, pLI 2.3028e-08, missense-Z 1.1287. *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 78.18, 38% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of STRA6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** STRA6's established molecular role includes retinol transmembrane transporter activity. In Reactome, STRA6 is annotated in disease pathway(s) including **Defective visual phototransduction due to STRA6 loss of function**.

**Disease mechanism (Reactome):** STRA6 loss or alteration is curated in [Defective visual phototransduction due to STRA6 loss of function](https://reactome.org/content/detail/R-HSA-9918449).

### Pathways affected {#pathways}

STRA6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective visual phototransduction due to STRA6 loss of function](https://reactome.org/content/detail/R-HSA-9918449) | other |
| [The canonical retinoid cycle in rods (twilight vision)](https://reactome.org/content/detail/R-HSA-2453902) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** retinol transmembrane transporter activity.

**Biological process:** blood vessel development, kidney development, pulmonary valve morphogenesis, ventricular septum development, heart development, learning.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (5 Likely benign, 2 Uncertain significance).

**Submission history:** 7 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-04-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

[microphthalmia, syndromic 9](https://sugi.bio/atlas/disease/microphthalmia-syndromic-9/).

**Reported phenotype names (ClinVar):** Microphthalmia, syndromic 9, not provided, not specified, AllHighlyPenetrant, PULMONARY AGENESIS, MICROPHTHALMIA, AND DIAPHRAGMATIC DEFECT, Matthew-Wood syndrome, ANOPHTHALMIA, CLINICAL, WITH MILD FACIAL DYSMORPHISM AND VARIABLE MALFORMATIONS OF THE LUNG, HEART, AND DIAPHRAGM, ANOPHTHALMIA/MICROPHTHALMIA AND PULMONARY HYPOPLASIA, SPEAR SYNDROME, none provided.

## Similar variants {#similar}

Related STRA6 variant pages (same residue, condition, or type): [STRA6 c.267-1G>T](/variant/stra6-c-267-minus-1g-t), [STRA6 p.Arg532Ter](/variant/stra6-p-arg532ter), [STRA6 p.Thr644Met](/variant/stra6-p-thr644met), [STRA6 c.*10A>C](/variant/stra6-c-star-10a-c), [STRA6 p.Ala54Ser](/variant/stra6-p-ala54ser), [STRA6 p.Ala557Val](/variant/stra6-p-ala557val), [STRA6 p.Arg467Cys](/variant/stra6-p-arg467cys), [STRA6 p.Arg655Cys](/variant/stra6-p-arg655cys).

### 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 287343). 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.*