Is CFI p.Ala153Thr (c.457G>A) pathogenic?

CFI p.Ala153Thr (c.457G>A) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-07). AlphaMissense: likely benign (0.176); Very rare (popmax 0.000254%, nfe); Associated with CFI-related disorder.

What condition is associated with CFI p.Ala153Thr (c.457G>A)?

CFI p.Ala153Thr (c.457G>A) is associated with CFI-related disorder (ClinVar).

How common is CFI p.Ala153Thr (c.457G>A) in the general population?

CFI p.Ala153Thr (c.457G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CFI p.Ala153Thr (c.457G>A)?

AlphaMissense predicts likely benign (score 0.176) — an in-silico prediction, not a clinical call.

CFI p.Ala153Thr

c.457G>A · rs2545449970 · VCV1979180

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.176	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -4.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000254% European (non-Finnish) · 3/1,179,998 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,798 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.Ala153Thr
Coding: c.457G>A
MANE Select: NM_000204
dbSNP: rs2545449970
Type: single nucleotide variant
Location: chr4:109764562 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 153: a disulfide bond; the srcr domain; an α-helix

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.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Trp145Ter Pathogenic ★★ same condition
CFI p.Ala76Gly Uncertain significance ★★ ⚠ same condition
CFI p.Arg317Gln Uncertain significance ★★ ⚠ same condition
CFI p.Arg502Cys Uncertain significance ★★ ⚠ same condition
CFI p.Asp224Asn Uncertain significance ★★ ⚠ same condition
CFI p.Asp524Tyr 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-ala153thr (accessed [today's date]).

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