Is CFH p.Leu1189Phe (c.3565C>T) pathogenic?

CFH p.Leu1189Phe (c.3565C>T) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.1539); Absent from gnomAD v4.1; Associated with hemolytic uremic syndrome, atypical, susceptibility to, 1.

How common is CFH p.Leu1189Phe (c.3565C>T) in the general population?

CFH p.Leu1189Phe (c.3565C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFH p.Leu1189Phe (c.3565C>T)?

AlphaMissense predicts likely benign (score 0.1539) — an in-silico prediction, not a clinical call.

CFH p.Leu1189Phe

Q: What condition is associated with CFH p.Leu1189Phe (c.3565C>T)?

CFH p.Leu1189Phe (c.3565C>T) is associated with hemolytic uremic syndrome, atypical, susceptibility to, 1, atypical hemolytic-uremic syndrome (ClinVar).

c.3565C>T · rs2149118712 · VCV1693716

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1539 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemolytic uremic syndrome, atypical, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1539	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -9.53	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 -14	GERP -3.7
Regional constraint	o/e 0.66	unconstrained · MANE · 3,752 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	0.035	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFH
Protein: p.Leu1189Phe
Coding: c.3565C>T
MANE Select: NM_000186
dbSNP: rs2149118712
Type: single nucleotide variant
Location: chr1:196747182 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 1189: a UniProt-annotated variant site (in ahus1); the sushi 20 domain; a β-strand; a disulfide bond

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

Disease context

hemolytic uremic syndrome, atypical, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome

Similar variants

CFH p.Leu1189Arg Likely pathogenic ★ ⚠ same residue
CFH p.Leu1189His Likely pathogenic ★ ⚠ same residue
CFH p.Leu1189Pro Likely pathogenic ★ ⚠ same residue
CFH p.Leu1189Ile Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same condition

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/cfh-p-leu1189phe (accessed [today's date]).

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