Is CFI p.Arg502His (c.1505G>A) pathogenic?

CFI p.Arg502His (c.1505G>A) is classified Uncertain significance in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-20). AlphaMissense: likely benign (0.2636); Ultra-rare (popmax 0.0164%, mid).

How common is CFI p.Arg502His (c.1505G>A) in the general population?

CFI p.Arg502His (c.1505G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CFI p.Arg502His (c.1505G>A)?

AlphaMissense predicts likely benign (score 0.2636) — an in-silico prediction, not a clinical call.

CFI p.Arg502His

c.1505G>A · rs927088953 · VCV1987058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2636	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -7.67	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 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	28.7	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00093% 15/1,613,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00801%	12,481
Admixed American	0.00334%	29,979
Remaining individualsnot grpmax-eligible	0.0016%	62,440
South Asian	0.0011%	91,072
European (non-Finnish)	0.000339%	294,807

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: CFI
Protein: p.Arg502His
Coding: c.1505G>A
MANE Select: NM_000204
dbSNP: rs927088953
Type: single nucleotide variant
Location: chr4:109742520 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 502: a disulfide bond; the peptidase s1 domain

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

Similar variants

CFI p.Arg502Cys Uncertain significance ★★ ⚠ same residue
CFI p.Arg502Gly Uncertain significance ★ ⚠ same residue
CFI p.Arg502Leu Uncertain significance ★ ⚠ same residue
CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same type
CFI c.57+1G>C Likely pathogenic ★★ same type
CFI c.658+1G>A Likely pathogenic ★★ same type
CFI c.905-1G>C Likely pathogenic ★★ same type
CFI p.Ala258Thr Pathogenic/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/cfi-p-arg502his (accessed [today's date]).

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