Is CFH p.Leu697Phe (c.2089C>T) pathogenic?

CFH p.Leu697Phe (c.2089C>T) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.452); Ultra-rare (popmax 0.0736%, eas); Associated with basal laminar drusen.

What condition is associated with CFH p.Leu697Phe (c.2089C>T)?

CFH p.Leu697Phe (c.2089C>T) is associated with basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1, complement factor H deficiency (ClinVar).

How common is CFH p.Leu697Phe (c.2089C>T) in the general population?

CFH p.Leu697Phe (c.2089C>T) is ultra-rare (popmax 0.0736%, eas) (gnomAD).

What do computational predictors say about CFH p.Leu697Phe (c.2089C>T)?

AlphaMissense predicts ambiguous (score 0.452) — an in-silico prediction, not a clinical call.

CFH p.Leu697Phe

c.2089C>T · rs201961184 · VCV1712460

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.452 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, eas)

Conditions

basal laminar drusen

Computational evidence

Protein change
AlphaMissense	0.452	ambiguous
REVEL	0.3	indeterminate
SaProt	—	withheld · numbering disagrees past residue 402 · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.96	GERP 0.12
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	19.51	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0736% East Asian · 33/44,846 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0471%

Overall 0.00254% 41/1,613,786 alleles · ultra-rare exomes 33/1,461,640 · genomes 8/152,146 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0736%	1,359
Remaining individualsnot grpmax-eligible	0.0048%	20,831
South Asian	0.0011%	91,078
European (non-Finnish)	0.000339%	294,957

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.Leu697Phe
Coding: c.2089C>T
MANE Select: NM_000186
dbSNP: rs201961184
Type: single nucleotide variant
Location: chr1:196726793 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 697: the sushi 12 domain

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

Disease context

basal laminar drusen — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency age related macular degeneration 4 atypical hemolytic-uremic syndrome

Similar variants

CFH p.Leu697= Likely benign ★ 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-leu697phe (accessed [today's date]).

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