Is CFB p.Val675Met (c.2023G>A) pathogenic?

CFB p.Val675Met (c.2023G>A) is classified Uncertain significance in CFB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-23). AlphaMissense: ambiguous (0.5149); Ultra-rare (popmax 0.0121%, sas); Associated with atypical hemolytic-uremic syndrome with B factor anomaly.

What condition is associated with CFB p.Val675Met (c.2023G>A)?

CFB p.Val675Met (c.2023G>A) is associated with atypical hemolytic-uremic syndrome with B factor anomaly (ClinVar).

How common is CFB p.Val675Met (c.2023G>A) in the general population?

CFB p.Val675Met (c.2023G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about CFB p.Val675Met (c.2023G>A)?

AlphaMissense predicts ambiguous (score 0.5149) — an in-silico prediction, not a clinical call.

CFB p.Val675Met

c.2023G>A · rs778556793 · VCV2671634

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

atypical hemolytic-uremic syndrome with B factor anomaly

Computational evidence

Protein change
AlphaMissense	0.5149	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -11.45	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	25.1	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 0.0121% South Asian · 11/91,088 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00112% 18/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,281
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000508%	196,673

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: CFB
Protein: p.Val675Met
Coding: c.2023G>A
MANE Select: NM_001710
dbSNP: rs778556793
Type: single nucleotide variant
Location: chr6:31951407 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 28 PDB
Residue 675: a disulfide bond; the peptidase s1 domain

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

Disease context

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

Similar variants

CFB c.-3G>A Uncertain significance ★★ same condition
CFB p.Arg203Gln Uncertain significance ★★ ⚠ same condition
CFB p.Glu621Lys Uncertain significance ★★ ⚠ same condition
CFB p.His508Gln Uncertain significance ★★ ⚠ same condition
CFB p.Lys306Arg Uncertain significance ★★ ⚠ same condition
CFB p.Pro168Leu Uncertain significance ★★ ⚠ same condition
CFB p.Pro33Ala Uncertain significance ★★ ⚠ same condition
CFB p.Tyr588His Uncertain significance ★★ ⚠ 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/cfb-p-val675met (accessed [today's date]).

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