Is CFH p.Arg257His (c.770G>A) pathogenic?

CFH p.Arg257His (c.770G>A) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0533); Ultra-rare (popmax 0.0179%, eas); Associated with basal laminar drusen.

What condition is associated with CFH p.Arg257His (c.770G>A)?

CFH p.Arg257His (c.770G>A) is associated with basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1, complement factor H deficiency (ClinVar).

How common is CFH p.Arg257His (c.770G>A) in the general population?

CFH p.Arg257His (c.770G>A) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about CFH p.Arg257His (c.770G>A)?

AlphaMissense predicts likely benign (score 0.0533) — an in-silico prediction, not a clinical call.

CFH p.Arg257His

c.770G>A · rs140107330 · VCV294487

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0533 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

basal laminar drusen

Computational evidence

Protein change
AlphaMissense	0.0533	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -6.87	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 -5.7	GERP -3.4
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	0.195	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 0.0179% East Asian · 8/44,730 alleles

Filtering AF 0.00886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00643%

Overall 0.00286% 46/1,610,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,591
African / African-American	0.00668%	14,979
Remaining individualsnot grpmax-eligible	0.00481%	20,773
European (non-Finnish)	0.00238%	42,074
Admixed American	0.00167%	59,778
South Asian	0.0011%	90,768

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.Arg257His
Coding: c.770G>A
MANE Select: NM_000186
dbSNP: rs140107330
Type: single nucleotide variant
Location: chr1:196679773 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 257: a β-strand; a disulfide bond; the sushi 4 domain

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

Disease context

basal laminar drusen — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CFH p.Arg257Cys 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-arg257his (accessed [today's date]).

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