Is CFAP65 c.645+1G>A pathogenic?

CFAP65 c.645+1G>A is classified Pathogenic in CFAP65 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-28). Very rare (popmax 0.000258%, nfe); Associated with spermatogenic failure 40.

What condition is associated with CFAP65 c.645+1G>A?

CFAP65 c.645+1G>A is associated with spermatogenic failure 40 (ClinVar).

How common is CFAP65 c.645+1G>A in the general population?

CFAP65 c.645+1G>A is very rare (popmax 0.000258%, nfe) (gnomAD).

CFAP65 c.645+1G>A

VCV4857359

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000258%, nfe)

Conditions

spermatogenic failure 40

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ0.99	donor loss · deltas
Pangolin	Δ0.82	loss · gain 0.41 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 0.74, phastCons 1
Non-coding constraint	Z 5.48	1 kb window · o/e 0.65 · regional · uncalibrated
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000258% European (non-Finnish) · 3/1,164,306 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00021% 3/1,430,824 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: CFAP65
Coding: c.645+1G>A
MANE Select: NM_194302
Type: single nucleotide variant
Location: chr2:219032469 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.03

Full CFAP65 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 40 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFAP65 p.Glu1781Ter Pathogenic ★ same condition
CFAP65 p.Ala497Thr Uncertain significance ★ ⚠ same condition
CFAP65 p.Arg762Ter Pathogenic same condition
CFAP65 p.Trp892Ter Pathogenic same condition
CFAP65 p.Gly155Ala Uncertain significance ⚠ same condition
CFAP65 p.Pro1477Ser Uncertain significance ⚠ same condition
CFAP65 p.Pro648Ser Uncertain significance ⚠ same condition
CFAP65 p.Ile1450fs Likely pathogenic ★ 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/cfap65-c-645-plus-1g-a (accessed [today's date]).

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