Is CFD p.Ile248Met (c.744C>G) pathogenic?

CFD p.Ile248Met (c.744C>G) is classified Benign/Likely benign in CFD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1775); Common (popmax 11.6%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CFD p.Ile248Met (c.744C>G)?

AlphaMissense predicts likely benign (score 0.1775) — an in-silico prediction, not a clinical call.

CFD p.Ile248Met

Q: How common is CFD p.Ile248Met (c.744C>G) in the general population?

CFD p.Ile248Met (c.744C>G) is common (popmax 11.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.744C>G · rs2230216 · VCV1170554

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1775 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1775	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.47	GERP -3.9
Regional constraint	o/e 1.40	unconstrained · MANE · 3,545 bp · p 9.1e-15 · regional, not allelic
Overall
CADD	21.0	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 11.6% East Asian · 4,903/42,242 alleles

Filtering AF 11.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.2%

Overall 0.581% 8,978/1,545,050 alleles · common exomes 7,850/1,392,832 · genomes 1,128/152,218 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	11.6%	9
South Asian	3.15%	32
Remaining individualsnot grpmax-eligible	1.16%	86
Admixed American	0.775%	129
Middle Eastern	0.183%	545
Ashkenazi Jewishnot grpmax-eligible	0.129%	775
African / African-American	0.122%	821
European (non-Finnish)	0.0151%	6,619

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.Ile248Met
Coding: c.744C>G
MANE Select: NM_001928
dbSNP: rs2230216
Type: single nucleotide variant
Location: chr19:863220 (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 248: a UniProt-annotated variant site (in); the peptidase s1 domain; an α-helix

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

Similar variants

CFD p.Ile248Val Uncertain significance ★ same residue
CFD p.Ile248= Likely benign ★ 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

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-ile248met (accessed [today's date]).

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