Is CFAP418 p.Leu22Pro (c.65T>C) pathogenic?

CFAP418 p.Leu22Pro (c.65T>C) is classified Uncertain significance in CFAP418 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-19). AlphaMissense: likely benign (0.0606); Very rare (popmax 0.000508%, nfe); Associated with bardet-biedl syndrome 21.

What condition is associated with CFAP418 p.Leu22Pro (c.65T>C)?

CFAP418 p.Leu22Pro (c.65T>C) is associated with bardet-biedl syndrome 21, cone-rod dystrophy 16, retinitis pigmentosa (ClinVar).

How common is CFAP418 p.Leu22Pro (c.65T>C) in the general population?

CFAP418 p.Leu22Pro (c.65T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

How is Bardet-Biedl syndrome inherited?

Typically Autosomal recessive, Oligogenic (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CFAP418 p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

CFAP418 p.Leu22Pro

c.65T>C · rs767780150 · VCV1681154

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

bardet-biedl syndrome 21

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -2.2, phastCons 0.002
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.91 · regional, not allelic
Overall
CADD	14.5	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 0.000508% European (non-Finnish) · 6/1,180,020 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,876 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: CFAP418
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_177965
dbSNP: rs767780150
Type: single nucleotide variant
Location: chr8:95269125 (GRCh38)
Gene constraint: LOEUF 1.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.73
Residue 22: the 'required for interaction with fam161a' region

Full CFAP418 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

bardet-biedl syndrome 21 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone-rod dystrophy 16 retinitis pigmentosa

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

CFAP418 p.Arg177Trp Pathogenic/Likely pathogenic ★★ same condition
CFAP418 p.Trp147Ter Pathogenic/Likely pathogenic ★★ same condition
CFAP418 c.*408G>A Uncertain significance ★★ same condition
CFAP418 c.*965C>G Uncertain significance ★★ same condition
CFAP418 p.Ala178Val Uncertain significance ★★ ⚠ same condition
CFAP418 p.Ala45Gly Uncertain significance ★★ ⚠ same condition
CFAP418 p.Arg177Gln Uncertain significance ★★ ⚠ same condition
CFAP418 p.Arg186Gly Uncertain significance ★★ ⚠ same condition

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/cfap418-p-leu22pro (accessed [today's date]).

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