Is CFH p.Arg1215Ter (c.3643C>T) pathogenic?

CFH p.Arg1215Ter (c.3643C>T) is classified Pathogenic/Likely pathogenic in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). Very rare (popmax 0.000339%, nfe); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Arg1215Ter (c.3643C>T)?

CFH p.Arg1215Ter (c.3643C>T) is associated with age related macular degeneration 4, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Arg1215Ter (c.3643C>T) in the general population?

CFH p.Arg1215Ter (c.3643C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

CFH p.Arg1215Ter

c.3643C>T · rs121913051 · VCV294526

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

age related macular degeneration 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (22 of 22) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -0.019
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,916 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,720 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)grpmax	0.000339%	294,979

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CFH
Protein: p.Arg1215Ter
Coding: c.3643C>T
MANE Select: NM_000186
dbSNP: rs121913051
Type: single nucleotide variant
Location: chr1:196747260 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 1215: a UniProt-annotated variant site (in ahus1); a UniProt-annotated variant site (in cfhd); the sushi 20 domain; a β-strand; a disulfide bond

Full CFH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: basal laminar drusen hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency atypical hemolytic-uremic syndrome

Similar variants

CFH p.Arg1215Leu Likely pathogenic ★★ ⚠ same residue
CFH p.Arg1215Gly Pathogenic ★ ⚠ same residue
CFH p.Arg1215Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH p.Arg1215= Likely benign ★★ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cfh-p-arg1215ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown