Is CFD p.Ile189Val (c.565A>G) pathogenic?

CFD p.Ile189Val (c.565A>G) is classified Uncertain significance in CFD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-11). AlphaMissense: likely benign (0.1339); Ultra-rare (popmax 0.0334%, mid).

How common is CFD p.Ile189Val (c.565A>G) in the general population?

CFD p.Ile189Val (c.565A>G) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about CFD p.Ile189Val (c.565A>G)?

AlphaMissense predicts likely benign (score 0.1339) — an in-silico prediction, not a clinical call.

CFD p.Ile189Val

c.565A>G · rs778236694 · VCV1163720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1339 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1339	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -0.54	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 -1.3	GERP -3.7
Regional constraint	o/e 1.40	unconstrained · MANE · 3,545 bp · p 9.1e-15 · regional, not allelic
Overall
CADD	7.725	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 0.0334% Middle Eastern · 2/5,992 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.0026% 41/1,576,590 alleles · ultra-rare exomes 37/1,424,528 · genomes 4/152,062 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,996
Remaining individualsnot grpmax-eligible	0.00326%	30,694
European (non-Finnish)	0.003%	33,387
Admixed American	0.00178%	56,274
South Asian	0.00113%	88,142

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: CFD
Protein: p.Ile189Val
Coding: c.565A>G
MANE Select: NM_001928
dbSNP: rs778236694
Type: single nucleotide variant
Location: chr19:861906 (GRCh38)
Gene constraint: LOEUF 1.948 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.19 · 40 PDB
Residue 189: the peptidase s1 domain

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

Similar variants

CFD p.Ile189Met Uncertain significance ★ same residue
CFD c.212+2T>G Likely pathogenic ★★ same type
CFD c.56-1G>C Likely pathogenic ★★ same type
CFD p.Tyr95Ter Pathogenic ★★ same type
ELANE p.Gly203Arg Pathogenic ★★ same type
ELANE p.Ser126Leu Pathogenic ★★ ⚠ same type
CFD p.Ala100Pro Uncertain significance ★★ same type
CFD p.Ala129Thr Uncertain significance ★★ ⚠ same type

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/cfd-p-ile189val (accessed [today's date]).

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