Is CFD p.Val251Gly (c.752T>G) pathogenic?

CFD p.Val251Gly (c.752T>G) is classified Uncertain significance in CFD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). AlphaMissense: ambiguous (0.4959); Very rare (popmax 0.00542%, afr).

How common is CFD p.Val251Gly (c.752T>G) in the general population?

CFD p.Val251Gly (c.752T>G) is very rare (popmax 0.00542%, afr) (gnomAD).

What do computational predictors say about CFD p.Val251Gly (c.752T>G)?

AlphaMissense predicts ambiguous (score 0.4959) — an in-silico prediction, not a clinical call.

CFD p.Val251Gly

c.752T>G · rs970281483 · VCV1986025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4959	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -13.78	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP 0.49, phastCons 0.25
Regional constraint	o/e 1.40	unconstrained · MANE · 3,545 bp · p 9.1e-15 · regional, not allelic
Overall
CADD	21.9	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 0.00542% African / African-American · 4/73,850 alleles

Filtering AF 0.00289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00258%

Overall 0.00323% 50/1,546,318 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00542%	18,463
European (non-Finnish)	0.00382%	26,193
Remaining individualsnot grpmax-eligible	0.00331%	30,225

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.Val251Gly
Coding: c.752T>G
MANE Select: NM_001928
dbSNP: rs970281483
Type: single nucleotide variant
Location: chr19:863228 (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 251: the peptidase s1 domain; an α-helix

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-val251gly (accessed [today's date]).

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