Is CFH p.Ile221Val (c.661A>G) pathogenic?

CFH p.Ile221Val (c.661A>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.0642); Ultra-rare (popmax 0.0501%, mid); Associated with complement factor H deficiency.

What condition is associated with CFH p.Ile221Val (c.661A>G)?

CFH p.Ile221Val (c.661A>G) is associated with complement factor H deficiency, age related macular degeneration 4, atypical hemolytic-uremic syndrome (ClinVar).

How common is CFH p.Ile221Val (c.661A>G) in the general population?

CFH p.Ile221Val (c.661A>G) is ultra-rare (popmax 0.0501%, mid) (gnomAD).

How is Immunodeficiency with factor H anomaly inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CFH p.Ile221Val (c.661A>G)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

CFH p.Ile221Val

c.661A>G · rs774239374 · VCV2077482

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement factor H deficiency

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9	GERP -3.4
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	0.001	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0501% Middle Eastern · 3/5,994 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00726%

Overall 0.00348% 56/1,607,306 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0501%	1,998
European (non-Finnish)	0.00417%	23,977
Remaining individualsnot grpmax-eligible	0.00322%	31,088
African / African-American	0.00268%	37,379

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.Ile221Val
Coding: c.661A>G
MANE Select: NM_000186
dbSNP: rs774239374
Type: single nucleotide variant
Location: chr1:196679664 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 221: a β-strand; a disulfide bond; the sushi 4 domain

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

Disease context

complement factor H deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 4 atypical hemolytic-uremic syndrome

For Immunodeficiency with factor H anomaly (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive

Similar variants

CFH p.Ile221Met 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.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-ile221val (accessed [today's date]).

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