# NM_005687.5(FARSB):c.198C>T (p.Asp66=)

https://sugi.bio/variant/farsb-p-asp66

## Summary

**FARSB p.Asp66= (c.198C>T)** is classified **Likely benign** in FARSB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). Ultra-rare (popmax 0.0495%, mid).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0495%, mid)

## For patients & families {#patients}

This is a change in the FARSB gene that is classified as likely benign — not considered disease-causing, 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 | [FARSB](https://sugi.bio/atlas/gene/FARSB/) |
| Protein change (HGVS p.) | p.Asp66= |
| Coding change (HGVS c.) | c.198C>T |
| MANE Select transcript | [NM_005687](https://www.ncbi.nlm.nih.gov/nuccore/NM_005687) |
| Variant type | single nucleotide variant |
| Location | chr2:222642922-222642922 (GRCh38) |
| ClinVar | [VCV4753202](https://www.ncbi.nlm.nih.gov/clinvar/variation/4753202/) |

**All HGVS expressions:** `NC_000002.11:g.223507641G>A`, `NC_000002.12:g.222642922G>A`, `NM_005687.5:c.198C>T`, `NR_130154.2:n.413C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.998 — fast-evolving / accelerated position
- CADD: **PHRED 13.28**. 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 **0.00**, acceptor gain **0.29**, donor gain **0.01**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.01**.
- Population frequency (gnomAD v4.1): grpmax **0.0495%** (mid) · FAF95 0.0134% · FAF99 0.00719% · 3/6,056 in the highest group · 61/1,612,008 alleles overall — ultra-rare (popmax 0.0495%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0495% | 2,019 |
| Remaining individuals (not grpmax-eligible) | 0.00961% | 10,405 |
| South Asian | 0.00769% | 13,000 |
| East Asian | 0.00446% | 22,426 |
| European (non-Finnish) | 0.0034% | 29,455 |
| African / African-American | 0.00267% | 37,500 |
| Admixed American | 0.00167% | 60,008 |

*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}

**FARSB** population constraint: LOEUF 1.131, pLI 0.0073883, missense-Z 0.31792. *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 **66** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.71, 92% of residues very-high.

**3 experimental structure(s)** (PDB): [3L4G](https://www.rcsb.org/structure/3L4G), [9UDL](https://www.rcsb.org/structure/9UDL), [9UDM](https://www.rcsb.org/structure/9UDM).

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

*Describes the biological roles of FARSB (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:** FARSB's established molecular role includes phenylalanine-tRNA ligase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cytosolic tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379716) | curated |

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

**Molecular function:** phenylalanine-tRNA ligase activity.

**Biological process:** phenylalanyl-tRNA aminoacylation, protein heterotetramerization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-26.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related FARSB variant pages (same residue, condition, or type): [FARSB c.848+1G>A](/variant/farsb-c-848-plus-1g-a), [FARSB p.Glu285Lys](/variant/farsb-p-glu285lys), [FARSB c.716-3C>T](/variant/farsb-c-716-minus-3c-t), [FARSB p.Ala287Gly](/variant/farsb-p-ala287gly), [FARSB p.Arg127Cys](/variant/farsb-p-arg127cys), [FARSB p.Arg127His](/variant/farsb-p-arg127his), [FARSB p.Arg135Leu](/variant/farsb-p-arg135leu), [FARSB p.Arg466Cys](/variant/farsb-p-arg466cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4753202). 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.*