Is CFHR4 p.Asp76= (c.228T>C) pathogenic?

CFHR4 p.Asp76= (c.228T>C) is classified Benign/Likely benign in CFHR4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-01). Low-frequency (popmax 1.4%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFHR4 p.Asp76= (c.228T>C)?

CFHR4 p.Asp76= (c.228T>C) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFHR4 p.Asp76= (c.228T>C) in the general population?

CFHR4 p.Asp76= (c.228T>C) is low-frequency (popmax 1.4%, nfe) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CFHR4 p.Asp76=

c.228T>C · rs145744152 · VCV788946

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.4%, nfe)

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -3.7
Overall
CADD	0.453	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.4% European (non-Finnish) · 16,544/1,179,126 alleles

Filtering AF 1.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.38%

Overall 1.15% 18,597/1,612,242 alleles · low-frequency exomes 17,323/1,460,728 · genomes 1,274/151,514 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.86%	54
European (non-Finnish)grpmax	1.4%	71
Remaining individualsnot grpmax-eligible	1.04%	96
Finnishnot grpmax-eligible	0.559%	179
Admixed American	0.549%	182
South Asian	0.471%	212
Middle Eastern	0.248%	404
African / African-American	0.247%	405
Ashkenazi Jewishnot grpmax-eligible	0.237%	423
East Asian	0.00223%	44,806

Amish 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: CFHR4
Protein: p.Asp76=
Coding: c.228T>C
MANE Select: NM_001201550
dbSNP: rs145744152
Type: single nucleotide variant
Location: chr1:196902587 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 76: the sushi 1 domain

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

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CFHR4 p.Tyr43Phe Likely benign ★★ same condition
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

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-asp76 (accessed [today's date]).

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