Is CFHR4 p.Trp445Ter (c.1334G>A) pathogenic?

CFHR4 p.Trp445Ter (c.1334G>A) is classified Likely benign in CFHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). Rare (popmax 0.974%, sas).

How common is CFHR4 p.Trp445Ter (c.1334G>A) in the general population?

CFHR4 p.Trp445Ter (c.1334G>A) is rare (popmax 0.974%, sas) (gnomAD).

CFHR4 p.Trp445Ter

c.1334G>A · VCV3380400

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.974%, sas)

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 8 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.6, phastCons 1
Overall
CADD	37.0	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 0.974% South Asian · 857/87,986 alleles

Filtering AF 0.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.898%

Overall 0.0576% 923/1,601,398 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.974%	103
Middle Eastern	0.0831%	1,204
Remaining individualsnot grpmax-eligible	0.058%	1,725
African / African-American	0.00408%	24,497
East Asian	0.00226%	44,296
European (non-Finnish)	0.00179%	55,994

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.Trp445Ter
Coding: c.1334G>A
MANE Select: NM_001201550
Type: single nucleotide variant
Location: chr1:196914648 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 445: a disulfide bond; the sushi 7 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.Trp68Ter Uncertain significance ★★ same type
CFHR4 p.Tyr238Ser Uncertain significance ★★ ⚠ same type
CFHR4 c.1180+4A>C Benign/Likely 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-trp445ter (accessed [today's date]).

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