Is CFH p.Ile622Val (c.1864A>G) pathogenic?

CFH p.Ile622Val (c.1864A>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0725); Very rare (popmax 0.00333%, amr); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Ile622Val (c.1864A>G)?

CFH p.Ile622Val (c.1864A>G) is associated with age related macular degeneration 4, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Ile622Val (c.1864A>G) in the general population?

CFH p.Ile622Val (c.1864A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CFH p.Ile622Val (c.1864A>G)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

CFH p.Ile622Val

c.1864A>G · rs990484984 · VCV1163676

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.8	GERP -0.71, phastCons 0.004
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	15.69	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 0.00333% Admixed American · 2/59,974 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,613,544 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,987
European (non-Finnish)	0.000509%	196,610

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.Ile622Val
Coding: c.1864A>G
MANE Select: NM_000186
dbSNP: rs990484984
Type: single nucleotide variant
Location: chr1:196725288 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 622: the sushi 10 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 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-ile622val (accessed [today's date]).

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