Is CFI p.Asp246Ala (c.737A>C) pathogenic?

CFI p.Asp246Ala (c.737A>C) is classified Uncertain significance in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.4896); Absent from gnomAD v4.1; Associated with CFI-related disorder.

What condition is associated with CFI p.Asp246Ala (c.737A>C)?

CFI p.Asp246Ala (c.737A>C) is associated with CFI-related disorder (ClinVar).

How common is CFI p.Asp246Ala (c.737A>C) in the general population?

CFI p.Asp246Ala (c.737A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFI p.Asp246Ala (c.737A>C)?

AlphaMissense predicts ambiguous (score 0.4896) — an in-silico prediction, not a clinical call.

CFI p.Asp246Ala

c.737A>C · VCV4280452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4896 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.4896	ambiguous
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -7.40	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	26.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFI
Protein: p.Asp246Ala
Coding: c.737A>C
MANE Select: NM_000204
Type: single nucleotide variant
Location: chr4:109760558 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 246: a binding site; a disulfide bond; the ldl-receptor class a 1 domain

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

Disease context

CFI-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFI p.Asp246= Likely benign ★ same residue
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Trp145Ter Pathogenic ★★ same condition
CFI p.Ala153Thr Uncertain significance ★★ ⚠ same condition
CFI p.Ala76Gly Uncertain significance ★★ ⚠ same condition
CFI p.Arg317Gln Uncertain significance ★★ ⚠ same condition
CFI p.Arg502Cys 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-asp246ala (accessed [today's date]).

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