Is CFHR2 p.Arg254Ter (c.760C>T) pathogenic?

CFHR2 p.Arg254Ter (c.760C>T) is classified Benign/Likely benign in CFHR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-08-16). Rare (popmax 0.745%, mid).

How common is CFHR2 p.Arg254Ter (c.760C>T) in the general population?

CFHR2 p.Arg254Ter (c.760C>T) is rare (popmax 0.745%, mid) (gnomAD).

CFHR2 p.Arg254Ter

c.760C>T · rs41313888 · VCV729791

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.745%, mid)

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
NMD	escapes	premature termination codon in the last exon (5 of 5) — 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 -3.6	GERP -2.3
Overall
CADD	34.0	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 0.745% Middle Eastern · 45/6,042 alleles

Filtering AF 0.572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.511%

Overall 0.058% 935/1,612,316 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.745%	134
Ashkenazi Jewishnot grpmax-eligible	0.548%	182
Admixed American	0.15%	665
Remaining individualsnot grpmax-eligible	0.119%	844
East Asian	0.047%	2,129
European (non-Finnish)	0.0432%	2,316
African / African-American	0.036%	2,777
South Asian	0.0077%	12,985

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: CFHR2
Protein: p.Arg254Ter
Coding: c.760C>T
MANE Select: NM_005666
dbSNP: rs41313888
Type: single nucleotide variant
Location: chr1:196959027 (GRCh38)
Gene constraint: LOEUF 1.498 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 4 PDB
Residue 254: a disulfide bond; a β-strand; the sushi 4 domain

Full CFHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR2 p.Arg254Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CFHR2 p.Val16Ala Uncertain significance ★★ ⚠ same type
CFHR2 c.430+141T>A Benign ★★ same type
CFHR2 c.430+20C>T Benign ★★ same type
CFHR2 c.430+7G>A Benign/Likely benign ★★ same type
CFHR2 c.431-48C>A Benign ★★ same type
CFHR2 c.431-65C>T Benign ★★ same type
CFHR2 c.58+129C>G Benign ★★ same type

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/cfhr2-p-arg254ter (accessed [today's date]).

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