Is CFH p.Ile492Val (c.1474A>G) pathogenic?

CFH p.Ile492Val (c.1474A>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-19). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.000509%, nfe); Associated with hemolytic uremic syndrome, atypical, susceptibility to, 1.

What condition is associated with CFH p.Ile492Val (c.1474A>G)?

CFH p.Ile492Val (c.1474A>G) is associated with hemolytic uremic syndrome, atypical, susceptibility to, 1, basal laminar drusen, complement factor H deficiency (ClinVar).

How common is CFH p.Ile492Val (c.1474A>G) in the general population?

CFH p.Ile492Val (c.1474A>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about CFH p.Ile492Val (c.1474A>G)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

CFH p.Ile492Val

c.1474A>G · rs892717090 · VCV1393028

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemolytic uremic syndrome, atypical, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -8.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.15	GERP -0.61
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	5.512	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 0.000509% European (non-Finnish) · 6/1,179,242 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,612,736 alleles · very rare

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.Ile492Val
Coding: c.1474A>G
MANE Select: NM_000186
dbSNP: rs892717090
Type: single nucleotide variant
Location: chr1:196713872 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 492: a β-strand; a disulfide bond; the sushi 8 domain

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

Disease context

hemolytic uremic syndrome, atypical, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: basal laminar drusen complement factor H deficiency age related macular degeneration 4

Similar variants

CFH p.Ile492= Likely benign ★ 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-ile492val (accessed [today's date]).

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