# NM_022369.4(STRA6):c.180A>G (p.Ser60=)

https://sugi.bio/variant/stra6-p-ser60

## Summary

**STRA6 p.Ser60= (c.180A>G)** is classified **Uncertain significance** in STRA6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-04). Rare (popmax 0.306%, eas); Associated with microphthalmia, syndromic 9.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs186185335 · 2 submitters · 1 linked condition · rare (popmax 0.306%, eas)

## For patients & families {#patients}

This is a change in the STRA6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Ser60= |
| Coding change (HGVS c.) | c.180A>G |
| MANE Select transcript | [NM_022369](https://www.ncbi.nlm.nih.gov/nuccore/NM_022369) |
| dbSNP | [rs186185335](https://www.ncbi.nlm.nih.gov/snp/rs186185335/) |
| Variant type | single nucleotide variant |
| Location | chr15:74197752-74197752 (GRCh38) |
| ClinVar | [VCV884974](https://www.ncbi.nlm.nih.gov/clinvar/variation/884974/) |

**All HGVS expressions:** `NC_000015.10:g.74197752T>C`, `NC_000015.9:g.74490093T>C`, `NG_009207.1:g.16279A>G`, `NG_054754.1:g.48T>C`, `NM_001142617.2:c.180A>G`, `NM_001142618.2:c.180A>G`, `NM_001142619.2:c.180A>G`, `NM_001142620.2:c.180A>G`, `NM_001199040.2:c.291A>G`, `NM_001199041.2:c.225A>G`, `NM_001199042.2:c.297A>G`, `NM_022369.4:c.180A>G`

## 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 **donor gain** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.289, GERP -1.51, phastCons 0.99 — weakly conserved position
- CADD: **PHRED 11.73**. 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 **0.07**, acceptor gain **0.00**, donor gain **0.29**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.29**.
- Population frequency (gnomAD v4.1): grpmax **0.306%** (eas) · FAF95 0.264% · FAF99 0.248% · 137/44,842 in the highest group · 170/1,613,330 alleles overall — rare (popmax 0.306%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.306% | 327 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.027% | 3,701 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,929 |
| European (non-Finnish) | 0.00153% | 65,555 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-08-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Microphthalmia, syndromic 9, PULMONARY AGENESIS, MICROPHTHALMIA, AND DIAPHRAGMATIC DEFECT, SPEAR SYNDROME, Matthew-Wood syndrome, ANOPHTHALMIA, CLINICAL, WITH MILD FACIAL DYSMORPHISM AND VARIABLE MALFORMATIONS OF THE LUNG, HEART, AND DIAPHRAGM, ANOPHTHALMIA/MICROPHTHALMIA AND PULMONARY HYPOPLASIA.

## 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 2026-10-06); 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 884974). 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.*