Is CFH p.Arg1078Ser (c.3234G>T) pathogenic?

CFH p.Arg1078Ser (c.3234G>T) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.2134); Very rare (popmax 0.00839%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFH p.Arg1078Ser (c.3234G>T)?

CFH p.Arg1078Ser (c.3234G>T) is associated with atypical hemolytic-uremic syndrome, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Arg1078Ser (c.3234G>T) in the general population?

CFH p.Arg1078Ser (c.3234G>T) is very rare (popmax 0.00839%, 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.

What do computational predictors say about CFH p.Arg1078Ser (c.3234G>T)?

AlphaMissense predicts likely benign (score 0.2134) — an in-silico prediction, not a clinical call.

CFH p.Arg1078Ser

c.3234G>T · rs121913062 · VCV16561

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00839%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.2134	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -3.4
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	0.113	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00839% European (non-Finnish) · 99/1,179,950 alleles

Filtering AF 0.00702% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00652%

Overall 0.00657% 106/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00839%	11,919
African / African-American	0.00534%	18,732
Remaining individualsnot grpmax-eligible	0.0048%	20,825

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.Arg1078Ser
Coding: c.3234G>T
MANE Select: NM_000186
dbSNP: rs121913062
Type: single nucleotide variant
Location: chr1:196743552 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 1078: a UniProt-annotated variant site (associated with basal laminar drusen); the sushi 18 domain; a disulfide bond

Full CFH 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

Also linked: basal laminar drusen hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency age related macular degeneration 4

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

CFH p.Arg1078Thr 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
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same condition
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg1215Leu 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-arg1078ser (accessed [today's date]).

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