Is CFHR4 p.Tyr43Phe (c.128A>T) pathogenic?

CFHR4 p.Tyr43Phe (c.128A>T) is classified Likely benign in CFHR4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.1314); Low-frequency (popmax 1.44%, sas); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFHR4 p.Tyr43Phe (c.128A>T)?

CFHR4 p.Tyr43Phe (c.128A>T) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFHR4 p.Tyr43Phe (c.128A>T) in the general population?

CFHR4 p.Tyr43Phe (c.128A>T) is low-frequency (popmax 1.44%, sas) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

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

What do computational predictors say about CFHR4 p.Tyr43Phe (c.128A>T)?

AlphaMissense predicts likely benign (score 0.1314) — an in-silico prediction, not a clinical call.

CFHR4 p.Tyr43Phe

c.128A>T · rs202234955 · VCV1712456

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1314 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.44%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.1314	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -9.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3.7
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	9.82	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.44% South Asian · 1,310/91,018 alleles

Filtering AF 1.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.35%

Overall 0.0869% 1,400/1,611,966 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.44%	69
Remaining individualsnot grpmax-eligible	0.12%	832
Middle Eastern	0.0165%	6,052
Admixed American	0.00501%	19,974
African / African-American	0.00269%	37,241
East Asian	0.00223%	44,814
European (non-Finnish)	0.000679%	147,357

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.Tyr43Phe
Coding: c.128A>T
MANE Select: NM_001201550
dbSNP: rs202234955
Type: single nucleotide variant
Location: chr1:196902487 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 43: 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.Asp76= Benign/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-tyr43phe (accessed [today's date]).

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