Is CFH p.Asn516Lys (c.1548T>A) pathogenic?

CFH p.Asn516Lys (c.1548T>A) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.2649); Ultra-rare (popmax 0.0826%, mid); Associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II.

What condition is associated with CFH p.Asn516Lys (c.1548T>A)?

CFH p.Asn516Lys (c.1548T>A) is associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Asn516Lys (c.1548T>A) in the general population?

CFH p.Asn516Lys (c.1548T>A) is ultra-rare (popmax 0.0826%, mid) (gnomAD).

What do computational predictors say about CFH p.Asn516Lys (c.1548T>A)?

AlphaMissense predicts likely benign (score 0.2649) — an in-silico prediction, not a clinical call.

CFH p.Asn516Lys

c.1548T>A · rs147403664 · VCV294493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Computational evidence

Protein change
AlphaMissense	0.2649	likely benign
REVEL	0.574	indeterminate
SaProt	LLR -10.84	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -0.87
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	14.2	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 0.0826% Middle Eastern · 5/6,050 alleles

Filtering AF 0.0547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0488%

Overall 0.018% 290/1,612,560 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0826%	1,210
Admixed American	0.0718%	1,392
Remaining individualsnot grpmax-eligible	0.024%	4,161
European (non-Finnish)	0.0188%	5,311
South Asian	0.00439%	22,765
African / African-American	0.00133%	74,958

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.Asn516Lys
Coding: c.1548T>A
MANE Select: NM_000186
dbSNP: rs147403664
Type: single nucleotide variant
Location: chr1:196715621 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 516: the sushi 9 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 hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency age related macular degeneration 4 atypical hemolytic-uremic syndrome

Similar variants

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
CFH p.Arg1215Ter 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-asn516lys (accessed [today's date]).

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