Is CFAP99 p.Arg459Cys (c.1375C>T) pathogenic?

CFAP99 p.Arg459Cys (c.1375C>T) is classified Uncertain significance in CFAP99 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). Ultra-rare (popmax 0.0808%, nfe).

How common is CFAP99 p.Arg459Cys (c.1375C>T) in the general population?

CFAP99 p.Arg459Cys (c.1375C>T) is ultra-rare (popmax 0.0808%, nfe) (gnomAD).

CFAP99 p.Arg459Cys

c.1375C>T · rs555838098 · VCV2382089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0808%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.091	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.8, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 36 kb · p 0.016 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0808% European (non-Finnish) · 926/1,146,730 alleles

Filtering AF 0.0764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0746%

Overall 0.0645% 991/1,535,638 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0808%	1,238
Remaining individualsnot grpmax-eligible	0.0467%	2,143
African / African-American	0.0273%	3,659
South Asian	0.0119%	8,404
Admixed American	0.00784%	12,747
East Asian	0.00489%	20,457
Finnishnot grpmax-eligible	0.00226%	44,244

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: CFAP99
Protein: p.Arg459Cys
Coding: c.1375C>T
MANE Select: NM_001193282
dbSNP: rs555838098
Type: single nucleotide variant
Location: chr4:2459178 (GRCh38)
Gene constraint: LOEUF 1.203 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.28

Full CFAP99 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP99 p.Ala255Thr Uncertain significance ★ same type
CFAP99 p.Ala307Thr Uncertain significance ★ same type
CFAP99 p.Ala366Thr Uncertain significance ★ same type
CFAP99 p.Ala369Gly Uncertain significance ★ same type
CFAP99 p.Ala396Val Uncertain significance ★ same type
CFAP99 p.Ala423Thr Uncertain significance ★ same type
CFAP99 p.Ala428Thr Uncertain significance ★ same type
CFAP99 p.Ala450Ser 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/cfap99-p-arg459cys (accessed [today's date]).

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