Is CFI p.Gly512Ser (c.1534G>A) pathogenic?

CFI p.Gly512Ser (c.1534G>A) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-30). AlphaMissense: likely pathogenic (0.7328); Very rare (popmax 0.00128%, nfe); Associated with CFI-related disorder.

What condition is associated with CFI p.Gly512Ser (c.1534G>A)?

CFI p.Gly512Ser (c.1534G>A) is associated with CFI-related disorder, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Gly512Ser (c.1534G>A) in the general population?

CFI p.Gly512Ser (c.1534G>A) is very rare (popmax 0.00128%, nfe) (gnomAD).

What do computational predictors say about CFI p.Gly512Ser (c.1534G>A)?

AlphaMissense predicts likely pathogenic (score 0.7328) — an in-silico prediction, not a clinical call.

CFI p.Gly512Ser

c.1534G>A · rs770828632 · VCV2734665

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00128%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.7328	likely pathogenic
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -10.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	35.0	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 0.00128% European (non-Finnish) · 15/1,168,262 alleles

Filtering AF 0.000771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000611%

Overall 0.00104% 15/1,448,906 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: CFI
Protein: p.Gly512Ser
Coding: c.1534G>A
MANE Select: NM_000204
dbSNP: rs770828632
Type: single nucleotide variant
Location: chr4:109742491 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 512: a β-strand; a disulfide bond; the peptidase s1 domain

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

Disease context

Also linked: atypical hemolytic-uremic syndrome with I factor anomaly

Similar variants

CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI c.57+1G>C Likely pathogenic ★★ same condition
CFI c.905-1G>C Likely pathogenic ★★ same condition
CFI p.Ala258Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Trp145Ter Pathogenic ★★ same condition
CFI c.773-3C>T 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/cfi-p-gly512ser (accessed [today's date]).

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