Is CFH p.Arg1210Cys (c.3628C>T) pathogenic?

CFH p.Arg1210Cys (c.3628C>T) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.4054); Ultra-rare (popmax 0.017%, nfe); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Arg1210Cys (c.3628C>T)?

CFH p.Arg1210Cys (c.3628C>T) is associated with age related macular degeneration 4, kidney disorder, basal laminar drusen (ClinVar).

How common is CFH p.Arg1210Cys (c.3628C>T) in the general population?

CFH p.Arg1210Cys (c.3628C>T) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

What do computational predictors say about CFH p.Arg1210Cys (c.3628C>T)?

AlphaMissense predicts ambiguous (score 0.4054) — an in-silico prediction, not a clinical call.

CFH p.Arg1210Cys

c.3628C>T · rs121913059 · VCV16558

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

ambiguous

0.4054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.4054	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -12.42	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.5
Regional constraint	o/e 0.66	unconstrained · MANE · 3,752 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	6.857	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 0.017% European (non-Finnish) · 200/1,179,908 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0137% 221/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.017%	5,900
Remaining individualsnot grpmax-eligible	0.016%	6,247
Admixed American	0.01%	10,000
African / African-American	0.004%	24,972
Finnishnot grpmax-eligible	0.00156%	64,028
South Asian	0.0011%	91,080

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.Arg1210Cys
Coding: c.3628C>T
MANE Select: NM_000186
dbSNP: rs121913059
Type: single nucleotide variant
Location: chr1:196747245 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 1210: a UniProt-annotated variant site (in cfhd and armd4; rare penetrant mutation that confers high risk of age-related macular degeneration); the sushi 20 domain; a disulfide bond

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

Disease context

Also linked: kidney disorder basal laminar drusen hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency atypical hemolytic-uremic syndrome inherited retinal dystrophy

Similar variants

CFH p.Arg1210Ser 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-arg1210cys (accessed [today's date]).

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