# NM_000350.3(ABCA4):c.1919C>T (p.Pro640Leu)

https://sugi.bio/variant/abca4-p-pro640leu

## Summary

**ABCA4 p.Pro640Leu (c.1919C>T)** is classified **Pathogenic/Likely pathogenic** in ABCA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-21). AlphaMissense: likely pathogenic (0.8302); Very rare (popmax 8.47e-05%, nfe); Associated with Stargardt disease.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs760790294 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ABCA4 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to Stargardt disease.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 50 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCA4 is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Stargardt disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Reduced visual acuity — Obligate (100%)
- Abnormal foveal morphology — Very frequent (99-80%)
- Color vision defect — Very frequent (99-80%)
- Central scotoma — Very frequent (99-80%)
- Macular degeneration — Very frequent (99-80%)
- Abnormal choroid morphology — Very frequent (99-80%)
- Abnormality of visual evoked potentials — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000181/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCA4](https://sugi.bio/atlas/gene/ABCA4/) |
| Protein change (HGVS p.) | p.Pro640Leu |
| Coding change (HGVS c.) | c.1919C>T |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| dbSNP | [rs760790294](https://www.ncbi.nlm.nih.gov/snp/rs760790294/) |
| Variant type | single nucleotide variant |
| Location | chr1:94062595-94062595 (GRCh38) |
| ClinVar | [VCV377403](https://www.ncbi.nlm.nih.gov/clinvar/variation/377403/) |

**All HGVS expressions:** `NC_000001.10:g.94528151G>A`, `NC_000001.11:g.94062595G>A`, `NG_009073.1:g.63555C>T`, `NG_009073.2:g.63553C>T`, `NM_000350.3:c.1919C>T`, `NM_001425324.1:c.1919C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8302) — concordant with the pathogenic call
- REVEL 0.875 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.793 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.876, GERP 1.96, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.0**. 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 0.98** across the covering region of the MANE Select transcript (93,993,240–94,121,045), spanning 127,805 bp. Chi-square p 0.24. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,028 in the highest group · 1/1,461,884 alleles overall — very rare (popmax 8.47e-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}

**ABCA4** population constraint: LOEUF 0.786, pLI 3.4822e-43, missense-Z 1.3815. *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):

- **ABCA4-related retinopathy** — Definitive (AR)
- **age related macular degeneration 2** — Disputed (AD)

## Protein context {#protein}

Residue **640** lies in a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 75.96, 10% of residues very-high.

**8 experimental structure(s)** (PDB): [7E7I](https://www.rcsb.org/structure/7E7I), [7E7O](https://www.rcsb.org/structure/7E7O), [7E7Q](https://www.rcsb.org/structure/7E7Q), [7LKP](https://www.rcsb.org/structure/7LKP), [7LKZ](https://www.rcsb.org/structure/7LKZ), [7M1P](https://www.rcsb.org/structure/7M1P).

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

*Describes the biological roles of ABCA4 (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:** ABCA4's established molecular role includes 11-cis retinal binding. In Reactome, ABCA4 is annotated in disease pathway(s) including **Defective visual phototransduction due to ABCA4 loss of function**.

**Disease mechanism (Reactome):** ABCA4 loss or alteration is curated in [Defective visual phototransduction due to ABCA4 loss of function](https://reactome.org/content/detail/R-HSA-9918454).

### Pathways affected {#pathways}

ABCA4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective visual phototransduction due to ABCA4 loss of function](https://reactome.org/content/detail/R-HSA-9918454) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [The canonical retinoid cycle in rods (twilight vision)](https://reactome.org/content/detail/R-HSA-2453902) | electronic |

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

**Molecular function:** 11-cis retinal binding, all-trans retinal binding, ATP hydrolysis activity, phosphatidylethanolamine flippase activity, flippase activity.

**Biological process:** retinal metabolic process, phospholipid translocation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-21.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-05-21 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-11 |

## Associated conditions {#conditions}

[Stargardt disease](https://sugi.bio/atlas/disease/stargardt-disease/).

**Reported phenotype names (ClinVar):** Stargardt disease, not provided, ABCA4-related disorder, none provided, Fundus flavimaculatus, Stargardt's disease, ABCA4-related disorders, ABCA4-related condition.

## Same-residue context {#hotspot}

Residue **640** carries **5 other pathogenic ClinVar variants** — a recurrently-mutated position: [ABCA4 p.Pro640Ser](/variant/abca4-p-pro640ser), [ABCA4 p.Pro640Arg](/variant/abca4-p-pro640arg), [ABCA4 p.Pro640Ala](/variant/abca4-p-pro640ala), [ABCA4 p.Pro640His](/variant/abca4-p-pro640his), [ABCA4 p.Pro640Thr](/variant/abca4-p-pro640thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCA4 variant pages (same residue, condition, or type): [ABCA4 p.Pro640Ser](/variant/abca4-p-pro640ser), [ABCA4 p.Pro640Ala](/variant/abca4-p-pro640ala), [ABCA4 p.Pro640Arg](/variant/abca4-p-pro640arg), [ABCA4 p.Pro640His](/variant/abca4-p-pro640his), [ABCA4 p.Pro640Thr](/variant/abca4-p-pro640thr), [ABCA4 c.4253+43G>A](/variant/abca4-c-4253-plus-43g-a), [ABCA4 c.4352+1G>A](/variant/abca4-c-4352-plus-1g-a), [ABCA4 c.5196+1137G>A](/variant/abca4-c-5196-plus-1137g-a).

### 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 377403). 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.*