Is CFH p.Arg257Cys (c.769C>T) pathogenic?

CFH p.Arg257Cys (c.769C>T) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-14). AlphaMissense: likely benign (0.1906); Very rare (popmax 0.00803%, afr); Associated with hemolytic uremic syndrome, atypical, susceptibility to, 1.

What condition is associated with CFH p.Arg257Cys (c.769C>T)?

CFH p.Arg257Cys (c.769C>T) is associated with hemolytic uremic syndrome, atypical, susceptibility to, 1, basal laminar drusen, complement factor H deficiency (ClinVar).

How common is CFH p.Arg257Cys (c.769C>T) in the general population?

CFH p.Arg257Cys (c.769C>T) is very rare (popmax 0.00803%, afr) (gnomAD).

What do computational predictors say about CFH p.Arg257Cys (c.769C>T)?

AlphaMissense predicts likely benign (score 0.1906) — an in-silico prediction, not a clinical call.

CFH p.Arg257Cys

c.769C>T · rs776887716 · VCV1162888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00803%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemolytic uremic syndrome, atypical, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1906	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -11.47	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -0.77
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	16.51	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 0.00803% African / African-American · 6/74,762 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000621% 10/1,610,706 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00803%	12,460
South Asian	0.0022%	45,377
European (non-Finnish)	0.00017%	589,011

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.Arg257Cys
Coding: c.769C>T
MANE Select: NM_000186
dbSNP: rs776887716
Type: single nucleotide variant
Location: chr1:196679772 (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

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

Also linked: basal laminar drusen complement factor H deficiency age related macular degeneration 4

Similar variants

CFH p.Arg257His Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C 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.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg232Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys 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-arg257cys (accessed [today's date]).

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