Is CFI p.Met508Ile (c.1524G>T) pathogenic?

CFI p.Met508Ile (c.1524G>T) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.9654); Very rare (popmax 0.00834%, amr); Associated with Inborn genetic diseases.

What condition is associated with CFI p.Met508Ile (c.1524G>T)?

CFI p.Met508Ile (c.1524G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CFI p.Met508Ile (c.1524G>T) in the general population?

CFI p.Met508Ile (c.1524G>T) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about CFI p.Met508Ile (c.1524G>T)?

AlphaMissense predicts likely pathogenic (score 0.9654) — an in-silico prediction, not a clinical call.

CFI p.Met508Ile

c.1524G>T · rs968428003 · VCV1162964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9654	likely pathogenic · top 9% in CFI
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -13.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00834% Admixed American · 5/59,952 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000435% 7/1,608,770 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,990
Remaining individualsnot grpmax-eligible	0.00321%	31,166

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.Met508Ile
Coding: c.1524G>T
MANE Select: NM_000204
dbSNP: rs968428003
Type: single nucleotide variant
Location: chr4:109742501 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 508: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFI p.Ala511Val Uncertain significance ★★ ⚠ same condition
CFI p.Asn102Ser Uncertain significance ★★ ⚠ same condition
CFI p.Glu109Lys Uncertain significance ★★ ⚠ same condition
CFI p.Glu445Asp Uncertain significance ★★ ⚠ same condition
CFI p.His401Gln Uncertain significance ★★ ⚠ same condition
CFI p.Ile126Thr Uncertain significance ★★ ⚠ same condition
CFI p.Leu491Arg Uncertain significance ★★ ⚠ same condition
CFI p.Lys69Glu 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-met508ile (accessed [today's date]).

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