Is CFH p.Ile372Val (c.1114A>G) pathogenic?

CFH p.Ile372Val (c.1114A>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.2539); Very rare (popmax 0.00446%, eas); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

How common is CFH p.Ile372Val (c.1114A>G) in the general population?

CFH p.Ile372Val (c.1114A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CFH p.Ile372Val (c.1114A>G)?

AlphaMissense predicts likely benign (score 0.2539) — an in-silico prediction, not a clinical call.

CFH p.Ile372Val

Q: What condition is associated with CFH p.Ile372Val (c.1114A>G)?

CFH p.Ile372Val (c.1114A>G) is associated with atypical hemolytic-uremic syndrome with I factor anomaly, atypical hemolytic-uremic syndrome (ClinVar).

c.1114A>G · rs1370184894 · VCV1275821

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.2539	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -1.8
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 5.4e-05 · regional, not allelic
Overall
CADD	6.585	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 0.00446% East Asian · 2/44,848 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,613,476 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.Ile372Val
Coding: c.1114A>G
MANE Select: NM_000186
dbSNP: rs1370184894
Type: single nucleotide variant
Location: chr1:196689569 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 372: a β-strand; a disulfide bond; the sushi 6 domain

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

Disease context

atypical hemolytic-uremic syndrome with I factor anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome

Similar variants

CFH c.1520-1G>A Pathogenic/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
CFH p.Arg232Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same condition
CFH p.Cys569Ter 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-ile372val (accessed [today's date]).

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