Is CFI p.His40Arg (c.119A>G) pathogenic?

CFI p.His40Arg (c.119A>G) is classified Uncertain significance in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0957); Very rare (popmax 0.00667%, amr); Associated with CFI-related disorder.

What condition is associated with CFI p.His40Arg (c.119A>G)?

CFI p.His40Arg (c.119A>G) is associated with CFI-related disorder (ClinVar).

How common is CFI p.His40Arg (c.119A>G) in the general population?

CFI p.His40Arg (c.119A>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CFI p.His40Arg (c.119A>G)?

AlphaMissense predicts likely benign (score 0.0957) — an in-silico prediction, not a clinical call.

CFI p.His40Arg

c.119A>G · VCV4280494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.0957	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -3.66	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 1.2	GERP -0.68, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	16.04	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 0.00667% Admixed American · 4/60,014 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000274% 4/1,461,862 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.His40Arg
Coding: c.119A>G
MANE Select: NM_000204
Type: single nucleotide variant
Location: chr4:109766763 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 40: a disulfide bond

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.His40Pro Uncertain significance ★ ⚠ 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-his40arg (accessed [today's date]).

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