Is CFAP65 p.Pro1729Arg (c.5186C>G) pathogenic?

CFAP65 p.Pro1729Arg (c.5186C>G) is classified Conflicting classifications of pathogenicity in CFAP65 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-07-30). AlphaMissense: likely benign (0.1995); Rare (popmax 0.271%, afr); Associated with Non-syndromic male infertility due to sperm motility disorder.

What condition is associated with CFAP65 p.Pro1729Arg (c.5186C>G)?

CFAP65 p.Pro1729Arg (c.5186C>G) is associated with Non-syndromic male infertility due to sperm motility disorder (ClinVar).

How common is CFAP65 p.Pro1729Arg (c.5186C>G) in the general population?

CFAP65 p.Pro1729Arg (c.5186C>G) is rare (popmax 0.271%, afr) (gnomAD).

What do computational predictors say about CFAP65 p.Pro1729Arg (c.5186C>G)?

AlphaMissense predicts likely benign (score 0.1995) — an in-silico prediction, not a clinical call.

CFAP65 p.Pro1729Arg

c.5186C>G · rs74775944 · VCV709633

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1995 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.271%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Non-syndromic male infertility due to sperm motility disorder

Computational evidence

Protein change
AlphaMissense	0.1995	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -7.12	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 2.3	GERP -1.9, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 23 kb · p 0.76 · regional, not allelic
Overall
CADD	18.83	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 0.271% African / African-American · 203/75,032 alleles

Filtering AF 0.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.228%

Overall 0.0131% 211/1,614,126 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.271%	370
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00333%	30,009
European (non-Finnish)	8.47e-05%	1,180,032

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.Pro1729Arg
Coding: c.5186C>G
MANE Select: NM_194302
dbSNP: rs74775944
Type: single nucleotide variant
Location: chr2:219004321 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.03
Residue 1729: a UniProt-annotated variant site (in spgf40)

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

Disease context

Non-syndromic male infertility due to sperm motility disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFAP65 p.Arg1231= Benign ★★ same type
CFAP65 p.Arg1545Gln Benign ★★ same type
CFAP65 p.Arg760Gln Benign ★★ same type
CFAP65 p.Asp1313= Likely benign ★★ same type
CFAP65 p.Leu1127= Benign/Likely benign ★★ same type
CFAP65 p.Leu1523= Benign/Likely benign ★★ same type
CFAP65 p.Leu1906= Benign/Likely benign ★★ same type
CFAP65 p.Lys1805= Likely benign ★★ 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/cfap65-p-pro1729arg (accessed [today's date]).

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