Is CFH p.Leu3Val (c.7C>G) pathogenic?

CFH p.Leu3Val (c.7C>G) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.0896); Rare (popmax 0.182%, mid); Associated with basal laminar drusen.

What condition is associated with CFH p.Leu3Val (c.7C>G)?

CFH p.Leu3Val (c.7C>G) is associated with basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1, complement factor H deficiency (ClinVar).

How common is CFH p.Leu3Val (c.7C>G) in the general population?

CFH p.Leu3Val (c.7C>G) is rare (popmax 0.182%, mid) (gnomAD).

What do computational predictors say about CFH p.Leu3Val (c.7C>G)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

CFH p.Leu3Val

c.7C>G · rs139254423 · VCV875857

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

basal laminar drusen

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.627	indeterminate
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.001	GERP -4.7
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	13.63	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 0.182% Middle Eastern · 11/6,058 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0787%

Overall 0.0189% 305/1,610,348 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	551
South Asian	0.089%	1,123
Remaining individualsnot grpmax-eligible	0.0208%	4,799
European (non-Finnish)	0.016%	6,259
Finnishnot grpmax-eligible	0.0141%	7,106
Admixed American	0.00333%	29,992
African / African-American	0.00133%	74,966

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.Leu3Val
Coding: c.7C>G
MANE Select: NM_000186
dbSNP: rs139254423
Type: single nucleotide variant
Location: chr1:196652124 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB

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

Similar variants

CFH p.Leu3Phe 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-leu3val (accessed [today's date]).

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