Is CFD p.Gln167His (c.501G>C) pathogenic?

CFD p.Gln167His (c.501G>C) is classified Uncertain significance in CFD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-08). AlphaMissense: ambiguous (0.52); Rare (popmax 0.298%, mid); Associated with CFD-related disorder.

What condition is associated with CFD p.Gln167His (c.501G>C)?

CFD p.Gln167His (c.501G>C) is associated with CFD-related disorder (ClinVar).

How common is CFD p.Gln167His (c.501G>C) in the general population?

CFD p.Gln167His (c.501G>C) is rare (popmax 0.298%, mid) (gnomAD).

What do computational predictors say about CFD p.Gln167His (c.501G>C)?

AlphaMissense predicts ambiguous (score 0.52) — an in-silico prediction, not a clinical call.

CFD p.Gln167His

c.501G>C · rs376221139 · VCV1037449

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.52 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.298%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CFD-related disorder

Computational evidence

Protein change
AlphaMissense	0.52	ambiguous
REVEL	0.121	moderately benign-leaning
SaProt	LLR -8.47	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -3.2, phastCons 0.015
Regional constraint	o/e 1.40	unconstrained · MANE · 3,545 bp · p 9.1e-15 · regional, not allelic
Overall
CADD	17.12	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 0.298% Middle Eastern · 18/6,040 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.00944% 151/1,600,124 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.298%	336
Admixed American	0.0586%	1,706
Remaining individualsnot grpmax-eligible	0.0273%	3,657
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,368
European (non-Finnish)	0.00628%	15,926
African / African-American	0.004%	24,999

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.Gln167His
Coding: c.501G>C
MANE Select: NM_001928
dbSNP: rs376221139
Type: single nucleotide variant
Location: chr19:861842 (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 167: a disulfide bond; the peptidase s1 domain; a β-strand

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

Disease context

CFD-related disorder

Similar variants

ELANE p.Ser126Leu Pathogenic ★★ ⚠ same condition
CFD c.212+1G>A Likely pathogenic ★ same condition
CFD c.55+1G>A Likely pathogenic ★ same condition
CFD c.-8G>A Likely benign same condition
CFD p.Glu89fs Likely pathogenic ★ same condition
CFD p.Val97fs Likely pathogenic ★ same condition
CFD c.212+2T>G Likely pathogenic ★★ same type
CFD c.56-1G>C Likely pathogenic ★★ 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-gln167his (accessed [today's date]).

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