# NM_007189.3(ABCF2):c.1531G>A (p.Val511Met)

https://sugi.bio/variant/abcf2-p-val511met

## Summary

**ABCF2 p.Val511Met (c.1531G>A)** is classified **Uncertain significance** in ABCF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely pathogenic (0.6002); Very rare (popmax 0.0011%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, nfe)

## For patients & families {#patients}

This is a change in the ABCF2 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 | [ABCF2](https://sugi.bio/atlas/gene/ABCF2/) |
| Protein change (HGVS p.) | p.Val511Met |
| Coding change (HGVS c.) | c.1531G>A |
| MANE Select transcript | [NM_007189](https://www.ncbi.nlm.nih.gov/nuccore/NM_007189) |
| Variant type | single nucleotide variant |
| Location | chr7:151215082-151215082 (GRCh38) |
| ClinVar | [VCV3410838](https://www.ncbi.nlm.nih.gov/clinvar/variation/3410838/) |

**All HGVS expressions:** `NC_000007.13:g.150912168C>T`, `NC_000007.14:g.151215082C>T`, `NG_084726.1:g.1294C>T`, `NM_005692.5:c.1531G>A`, `NM_007189.3:c.1531G>A`, `NR_160983.1:n.1616G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6002)
- REVEL 0.482 (indeterminate)
- SaProt LLR -8.46 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.582, GERP 1.53, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.6**. 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 0.56** across the covering region of the MANE Select transcript (151,214,057–151,218,866), spanning 4,809 bp. Chi-square p 1.3e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.38 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.43** (loss), gain 0.33 / loss 0.43. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (nfe) · FAF95 0.000615% · FAF99 0.000474% · 13/1,179,204 in the highest group · 13/1,460,112 alleles overall — very rare (popmax 0.0011%, 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}

**ABCF2** population constraint: LOEUF 0.61, pLI 0.0033779, missense-Z 3.7095. *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 **511** lies in the abc transporter 2 domain.

AlphaFold model confidence (whole protein): pLDDT 83.57, 45% of residues very-high.

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

*Describes the biological roles of ABCF2 (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.*


### Pathways affected {#pathways}

ABCF2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NFE2L2 regulating MDR associated enzymes](https://reactome.org/content/detail/R-HSA-9818032) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-28.

**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 | 2024-10-28 |

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

## Similar variants {#similar}

Related ABCF2 variant pages (same residue, condition, or type): [ABCF2 p.Arg113His](/variant/abcf2-p-arg113his), [ABCF2 p.Arg223His](/variant/abcf2-p-arg223his), [ABCF2 p.Asp166Asn](/variant/abcf2-p-asp166asn), [ABCF2 p.Asp202Asn](/variant/abcf2-p-asp202asn), [ABCF2 p.Asp519Asn](/variant/abcf2-p-asp519asn), [ABCF2 p.Gln399His](/variant/abcf2-p-gln399his), [ABCF2 p.Glu373Asp](/variant/abcf2-p-glu373asp), [ABCF2 p.Glu550Lys](/variant/abcf2-p-glu550lys).

### 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 3410838). 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.*