Is CFAP46 p.Leu2173Pro (c.6518T>C) pathogenic?

CFAP46 p.Leu2173Pro (c.6518T>C) is classified Uncertain significance in CFAP46 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely pathogenic (0.8374); Very rare (popmax 0.00017%, nfe).

How common is CFAP46 p.Leu2173Pro (c.6518T>C) in the general population?

CFAP46 p.Leu2173Pro (c.6518T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CFAP46 p.Leu2173Pro (c.6518T>C)?

AlphaMissense predicts likely pathogenic (score 0.8374) — an in-silico prediction, not a clinical call.

CFAP46 p.Leu2173Pro

c.6518T>C · rs2539333485 · VCV2527074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
AlphaMissense	0.8374	likely pathogenic · top 6% in CFAP46
REVEL	0.405	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 134 kb · p 0.00093 · regional, not allelic
Overall
CADD	23.8	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 0.00017% European (non-Finnish) · 2/1,179,922 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,358 alleles · very rare

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: CFAP46
Protein: p.Leu2173Pro
Coding: c.6518T>C
MANE Select: NM_001200049
dbSNP: rs2539333485
Type: single nucleotide variant
Location: chr10:132836835 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)

Full CFAP46 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP46 p.Ala1708Val Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1742Glu Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1742Val Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1746Glu Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1788Val Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1806Val Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1811Val Uncertain significance ★ ⚠ same type
CFAP46 p.Ala1871Val 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/cfap46-p-leu2173pro (accessed [today's date]).

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