# NM_198179.3(QRFPR):c.1055T>C (p.Val352Ala)

https://sugi.bio/variant/qrfpr-p-val352ala

## Summary

**QRFPR p.Val352Ala (c.1055T>C)** is classified **Uncertain significance** in QRFPR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1015); Very rare (popmax 0.0011%, sas).

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

## For patients & families {#patients}

This is a change in the QRFPR 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 | [QRFPR](https://sugi.bio/atlas/gene/QRFPR/) |
| Protein change (HGVS p.) | p.Val352Ala |
| Coding change (HGVS c.) | c.1055T>C |
| MANE Select transcript | [NM_198179](https://www.ncbi.nlm.nih.gov/nuccore/NM_198179) |
| Variant type | single nucleotide variant |
| Location | chr4:121329555-121329555 (GRCh38) |
| ClinVar | [VCV4574711](https://www.ncbi.nlm.nih.gov/clinvar/variation/4574711/) |

**All HGVS expressions:** `NC_000004.11:g.122250710A>G`, `NC_000004.12:g.121329555A>G`, `NM_198179.3:c.1055T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1015)
- REVEL 0.144 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.803 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.499, GERP 1.9, phastCons 0.002 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 13.29**. 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 1.02** across the covering region of the MANE Select transcript (121,329,317–121,380,647), spanning 51,330 bp. Chi-square p 0.68. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 21 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.0005% · FAF99 0.000366% · 1/90,992 in the highest group · 12/1,613,708 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 90,992 |
| European (non-Finnish) | 0.000932% | 107,263 |

*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}

**QRFPR** population constraint: LOEUF 1.532, pLI 6.2738e-12, missense-Z 0.1451. *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 78.74, 45% of residues very-high.

**2 experimental structure(s)** (PDB): [8WZ2](https://www.rcsb.org/structure/8WZ2), [8ZH8](https://www.rcsb.org/structure/8ZH8).

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

*Describes the biological roles of QRFPR (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:** QRFPR's established molecular role includes G protein-coupled receptor activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Orexin and neuropeptides FF and QRFP bind to their respective receptors](https://reactome.org/content/detail/R-HSA-389397) | curated |

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

**Molecular function:** G protein-coupled receptor activity.

**Biological process:** G protein-coupled receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-21.

**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 | 2025-10-21 |

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

## Similar variants {#similar}

Related QRFPR variant pages (same residue, condition, or type): [QRFPR p.Val352Ile](/variant/qrfpr-p-val352ile), [QRFPR p.Ile296Thr](/variant/qrfpr-p-ile296thr), [QRFPR p.Ala128Thr](/variant/qrfpr-p-ala128thr), [QRFPR p.Ala315Val](/variant/qrfpr-p-ala315val), [QRFPR p.Arg13Trp](/variant/qrfpr-p-arg13trp), [QRFPR p.Arg160Gln](/variant/qrfpr-p-arg160gln), [QRFPR p.Arg161Thr](/variant/qrfpr-p-arg161thr), [QRFPR p.Arg16Pro](/variant/qrfpr-p-arg16pro).

### 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 4574711). 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.*