Is CFI p.Arg448His (c.1343G>A) pathogenic?

CFI p.Arg448His (c.1343G>A) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-03). AlphaMissense: likely benign (0.0638); Ultra-rare (popmax 0.0944%, sas); Associated with Inborn genetic diseases.

What condition is associated with CFI p.Arg448His (c.1343G>A)?

CFI p.Arg448His (c.1343G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CFI p.Arg448His (c.1343G>A) in the general population?

CFI p.Arg448His (c.1343G>A) is ultra-rare (popmax 0.0944%, sas) (gnomAD).

What do computational predictors say about CFI p.Arg448His (c.1343G>A)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

CFI p.Arg448His

c.1343G>A · rs139952851 · VCV1645653

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0944%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -3.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.31	GERP -3.5
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	4.384	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 0.0944% South Asian · 86/91,086 alleles

Filtering AF 0.0782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0723%

Overall 0.0075% 121/1,614,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0944%	1,059
Admixed American	0.0317%	3,158
African / African-American	0.00533%	18,761
East Asian	0.00223%	44,888
European (non-Finnish)	0.000932%	107,275

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.Arg448His
Coding: c.1343G>A
MANE Select: NM_000204
dbSNP: rs139952851
Type: single nucleotide variant
Location: chr4:109746308 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 448: 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.Arg448Cys Uncertain significance ★★ ⚠ same residue
CFI p.Arg448Leu Uncertain significance ★ ⚠ same residue
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

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-arg448his (accessed [today's date]).

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