Is CFH p.Pro418Ser (c.1252C>T) pathogenic?

CFH p.Pro418Ser (c.1252C>T) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0924); Ultra-rare (popmax 0.084%, afr); Associated with Inborn genetic diseases.

What condition is associated with CFH p.Pro418Ser (c.1252C>T)?

CFH p.Pro418Ser (c.1252C>T) is associated with Inborn genetic diseases, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Pro418Ser (c.1252C>T) in the general population?

CFH p.Pro418Ser (c.1252C>T) is ultra-rare (popmax 0.084%, afr) (gnomAD).

What do computational predictors say about CFH p.Pro418Ser (c.1252C>T)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

CFH p.Pro418Ser

c.1252C>T · rs369496377 · VCV2161403

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.084%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -5.72	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 -20	GERP -3.8
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	0.001	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 0.084% African / African-American · 63/74,994 alleles

Filtering AF 0.0674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0613%

Overall 0.00415% 67/1,613,436 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.084%	1,190
Admixed American	0.00501%	19,963
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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: CFH
Protein: p.Pro418Ser
Coding: c.1252C>T
MANE Select: NM_000186
dbSNP: rs369496377
Type: single nucleotide variant
Location: chr1:196690155 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 418: a disulfide bond; the sushi 7 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hemolytic uremic syndrome, atypical, susceptibility to, 1

Similar variants

CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same condition
CFH p.Gln859Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Glu625Ter Pathogenic ★★ same condition
CFH p.Gly1204Ter Pathogenic ★★ same condition
CFH p.Ser1191Leu 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-pro418ser (accessed [today's date]).

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