Is CFI p.Ala258Thr (c.772G>A) pathogenic?

CFI p.Ala258Thr (c.772G>A) is classified Pathogenic/Likely pathogenic in CFI (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-08-10). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.0146%, nfe); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Ala258Thr (c.772G>A)?

CFI p.Ala258Thr (c.772G>A) is associated with atypical hemolytic-uremic syndrome with I factor anomaly, complement factor I deficiency, age related macular degeneration 13 (ClinVar).

How common is CFI p.Ala258Thr (c.772G>A) in the general population?

CFI p.Ala258Thr (c.772G>A) is ultra-rare (popmax 0.0146%, nfe) (gnomAD).

What do computational predictors say about CFI p.Ala258Thr (c.772G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

CFI p.Ala258Thr

c.772G>A · rs199688124 · VCV1451295

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0146%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign ⚠ discordant with ClinVar
REVEL	0.387	indeterminate
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.81	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.73	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	27.2	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 0.0146% European (non-Finnish) · 166/1,137,654 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.0114% 178/1,567,416 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0146%	6,853
Finnishnot grpmax-eligible	0.00938%	10,666
Remaining individualsnot grpmax-eligible	0.00657%	15,231
African / African-American	0.00271%	36,931

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.Ala258Thr
Coding: c.772G>A
MANE Select: NM_000204
dbSNP: rs199688124
Type: single nucleotide variant
Location: chr4:109760523 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 258: the ldl-receptor class a 2 domain; a β-strand

Full CFI 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: complement factor I deficiency age related macular degeneration 13

Similar variants

CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI c.57+1G>C Likely pathogenic ★★ same condition
CFI c.658+1G>A Likely pathogenic ★★ same condition
CFI c.905-1G>C Likely pathogenic ★★ same condition
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI c.773-3C>T Uncertain significance ★★ same condition
CFI c.940+6C>A 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-ala258thr (accessed [today's date]).

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