Is CFHR4 p.Trp68Ter (c.204G>A) pathogenic?

CFHR4 p.Trp68Ter (c.204G>A) is classified Uncertain significance in CFHR4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). Rare (popmax 0.121%, afr).

How common is CFHR4 p.Trp68Ter (c.204G>A) in the general population?

CFHR4 p.Trp68Ter (c.204G>A) is rare (popmax 0.121%, afr) (gnomAD).

CFHR4 p.Trp68Ter

c.204G>A · rs201480125 · VCV2503967

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.121%, afr)

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	predicted	premature termination codon in exon 2 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP 0.064
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 0.121% African / African-American · 90/74,372 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0933%

Overall 0.0107% 173/1,612,170 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.121%	826
Remaining individualsnot grpmax-eligible	0.0128%	7,804
Admixed American	0.00668%	14,964
European (non-Finnish)	0.00602%	16,610

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: CFHR4
Protein: p.Trp68Ter
Coding: c.204G>A
MANE Select: NM_001201550
dbSNP: rs201480125
Type: single nucleotide variant
Location: chr1:196902563 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 68: the sushi 1 domain

Full CFHR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR4 p.Ala159Val Uncertain significance ★★ ⚠ same type
CFHR4 p.Arg40His Uncertain significance ★★ ⚠ same type
CFHR4 p.Ile318Thr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser199Tyr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser507Leu Uncertain significance ★★ ⚠ same type
CFHR4 p.Tyr238Ser Uncertain significance ★★ ⚠ same type
CFHR4 c.1180+4A>C Benign/Likely benign ★★ same type
CFHR4 c.1181-156T>A 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/cfhr4-p-trp68ter (accessed [today's date]).

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