# NM_001201550.3(CFHR4):c.121A>T (p.Arg41Ter)

https://sugi.bio/variant/cfhr4-p-arg41ter

## Summary

**CFHR4 p.Arg41Ter (c.121A>T)** is classified **Conflicting classifications of pathogenicity** in CFHR4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-06). Rare (popmax 0.263%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · rare (popmax 0.263%, afr)

## For patients & families {#patients}

This is a change in the CFHR4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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 | [CFHR4](https://sugi.bio/atlas/gene/CFHR4/) |
| Protein change (HGVS p.) | p.Arg41Ter |
| Coding change (HGVS c.) | c.121A>T |
| MANE Select transcript | [NM_001201550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001201550) |
| Variant type | single nucleotide variant |
| Location | chr1:196902480-196902480 (GRCh38) |
| ClinVar | [VCV3385301](https://www.ncbi.nlm.nih.gov/clinvar/variation/3385301/) |

**All HGVS expressions:** `LRG_1224:g.19467A>T`, `LRG_1224t1:c.121A>T`, `NC_000001.10:g.196871610A>T`, `NC_000001.11:g.196902480A>T`, `NG_028159.1:g.19467A>T`, `NM_001201550.3:c.121A>T`, `NM_001201551.2:c.118A>T`, `NM_006684.5:c.121A>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 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.881, GERP 0.513 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.204, pLI 1.3755e-19. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.263%** (afr) · FAF95 0.233% · FAF99 0.221% · 196/74,498 in the highest group · 226/1,612,054 alleles overall — rare (popmax 0.263%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.263% | 380 |
| Remaining individuals (not grpmax-eligible) | 0.0272% | 3,672 |
| Admixed American | 0.0167% | 5,992 |
| South Asian | 0.0033% | 30,340 |

*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}

**CFHR4** population constraint: LOEUF 1.204, pLI 1.3755e-19, missense-Z 0.58343. *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 **41** lies in the sushi 1 domain.

AlphaFold model confidence (whole protein): pLDDT 87.75, 51% of residues very-high.

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

*Describes the biological roles of CFHR4 (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}

CFHR4 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-06.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2025–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-05 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-06 |

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

## Similar variants {#similar}

Related CFHR4 variant pages (same residue, condition, or type): [CFHR4 p.Ala159Val](/variant/cfhr4-p-ala159val), [CFHR4 p.Arg40His](/variant/cfhr4-p-arg40his), [CFHR4 p.Ile318Thr](/variant/cfhr4-p-ile318thr), [CFHR4 p.Ser199Tyr](/variant/cfhr4-p-ser199tyr), [CFHR4 p.Ser507Leu](/variant/cfhr4-p-ser507leu), [CFHR4 p.Trp68Ter](/variant/cfhr4-p-trp68ter), [CFHR4 p.Tyr238Ser](/variant/cfhr4-p-tyr238ser), [CFHR4 c.1180+4A>C](/variant/cfhr4-c-1180-plus-4a-c).

### 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 3385301). 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.*