Is CFD p.Val56Leu (c.166G>C) pathogenic?

CFD p.Val56Leu (c.166G>C) is classified Uncertain significance in CFD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.151); Absent from gnomAD v4.1.

How common is CFD p.Val56Leu (c.166G>C) in the general population?

CFD p.Val56Leu (c.166G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFD p.Val56Leu (c.166G>C)?

AlphaMissense predicts likely benign (score 0.151) — an in-silico prediction, not a clinical call.

CFD p.Val56Leu

c.166G>C · VCV4653036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.151 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.151	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -7.12	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 -0.49	GERP -4.7, phastCons 0.003
Regional constraint	o/e 1.40	unconstrained · MANE · 3,545 bp · p 9.1e-15 · regional, not allelic
Overall
CADD	15.44	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

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: CFD
Protein: p.Val56Leu
Coding: c.166G>C
MANE Select: NM_001928
Type: single nucleotide variant
Location: chr19:860727 (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 56: the peptidase s1 domain; a β-strand; a disulfide bond

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

Similar variants

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
CFD p.Ala143Val 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-val56leu (accessed [today's date]).

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