Is CFH p.Ser884Tyr (c.2651C>A) pathogenic?

CFH p.Ser884Tyr (c.2651C>A) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.1206); Rare (popmax 0.375%, afr); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Ser884Tyr (c.2651C>A)?

CFH p.Ser884Tyr (c.2651C>A) is associated with age related macular degeneration 4, basal laminar drusen, complement factor H deficiency (ClinVar).

How common is CFH p.Ser884Tyr (c.2651C>A) in the general population?

CFH p.Ser884Tyr (c.2651C>A) is rare (popmax 0.375%, afr) (gnomAD).

What do computational predictors say about CFH p.Ser884Tyr (c.2651C>A)?

AlphaMissense predicts likely benign (score 0.1206) — an in-silico prediction, not a clinical call.

CFH p.Ser884Tyr

c.2651C>A · rs114743644 · VCV724330

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1206 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.375%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.1206	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -8.10	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 -0.99	GERP 1.7
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	8.252	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 0.375% African / African-American · 281/74,984 alleles

Filtering AF 0.339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.325%

Overall 0.0188% 304/1,613,246 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.375%	267
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Admixed American	0.0167%	5,998
European (non-Finnish)	0.00017%	589,744

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.Ser884Tyr
Coding: c.2651C>A
MANE Select: NM_000186
dbSNP: rs114743644
Type: single nucleotide variant
Location: chr1:196737529 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 884: the sushi 15 domain; a β-strand; a disulfide bond

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

Disease context

Also linked: basal laminar drusen complement factor H deficiency atypical hemolytic-uremic syndrome

Similar variants

CFH p.Ser884Pro 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-ser884tyr (accessed [today's date]).

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