Is CFAP65 p.Pro1477Ser (c.4429C>T) pathogenic?

CFAP65 p.Pro1477Ser (c.4429C>T) is classified Uncertain significance in CFAP65 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-24). AlphaMissense: likely benign (0.1025); Ultra-rare (popmax 0.0165%, mid); Associated with spermatogenic failure 40.

What condition is associated with CFAP65 p.Pro1477Ser (c.4429C>T)?

CFAP65 p.Pro1477Ser (c.4429C>T) is associated with spermatogenic failure 40 (ClinVar).

How common is CFAP65 p.Pro1477Ser (c.4429C>T) in the general population?

CFAP65 p.Pro1477Ser (c.4429C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CFAP65 p.Pro1477Ser (c.4429C>T)?

AlphaMissense predicts likely benign (score 0.1025) — an in-silico prediction, not a clinical call.

CFAP65 p.Pro1477Ser

c.4429C>T · rs1326462759 · VCV2664048

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1025 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spermatogenic failure 40

Computational evidence

Protein change
AlphaMissense	0.1025	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3	GERP -1.5, phastCons 0.64
Regional constraint	o/e 0.99	unconstrained · MANE · 23 kb · p 0.76 · regional, not allelic
Overall
CADD	9.501	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 0.0165% Middle Eastern · 1/6,058 alleles

Overall 0.000124% 2/1,612,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
European (non-Finnish)	8.48e-05%	1,179,359

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
Protein: p.Pro1477Ser
Coding: c.4429C>T
MANE Select: NM_194302
dbSNP: rs1326462759
Type: single nucleotide variant
Location: chr2:219009965 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.03
Residue 1477: a UniProt-annotated variant site (in spgf40)

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 c.645+1G>A Pathogenic ★ same condition
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.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-p-pro1477ser (accessed [today's date]).

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