Is CFH p.Gln476= (c.1428A>G) pathogenic?

CFH p.Gln476= (c.1428A>G) is classified Benign in CFH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 5.08%, afr) — too common for a highly-penetrant pathogenic allele; Associated with age related macular degeneration 4.

What condition is associated with CFH p.Gln476= (c.1428A>G)?

CFH p.Gln476= (c.1428A>G) is associated with age related macular degeneration 4, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

CFH p.Gln476=

Q: How common is CFH p.Gln476= (c.1428A>G) in the general population?

CFH p.Gln476= (c.1428A>G) is common (popmax 5.08%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1428A>G · rs34399588 · VCV294492

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 5.08%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

age related macular degeneration 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3.7
Overall
CADD	0.466	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.08% African / African-American · 3,805/74,942 alleles

Filtering AF 4.94% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.89%

Overall 0.282% 4,540/1,612,462 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.08%	20
Admixed American	0.436%	229
Remaining individualsnot grpmax-eligible	0.343%	292
Middle Eastern	0.165%	605
South Asian	0.0571%	1,751
European (non-Finnish)	0.0168%	5,954

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.Gln476=
Coding: c.1428A>G
MANE Select: NM_000186
dbSNP: rs34399588
Type: single nucleotide variant
Location: chr1:196713826 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 476: a β-strand; a disulfide bond; the sushi 8 domain

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

Disease context

Also linked: basal laminar drusen hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency

Similar variants

CFH p.Gln476Leu Uncertain significance ★ ⚠ 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-gln476 (accessed [today's date]).

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