Is CFAP61 p.Arg552Cys (c.1654C>T) pathogenic?

CFAP61 p.Arg552Cys (c.1654C>T) is classified Pathogenic/Likely pathogenic in CFAP61 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-29). AlphaMissense: likely benign (0.1707); Ultra-rare (popmax 0.0824%, eas); Associated with spermatogenic failure 84.

What condition is associated with CFAP61 p.Arg552Cys (c.1654C>T)?

CFAP61 p.Arg552Cys (c.1654C>T) is associated with spermatogenic failure 84, situs inversus (ClinVar).

How common is CFAP61 p.Arg552Cys (c.1654C>T) in the general population?

CFAP61 p.Arg552Cys (c.1654C>T) is ultra-rare (popmax 0.0824%, eas) (gnomAD).

What do computational predictors say about CFAP61 p.Arg552Cys (c.1654C>T)?

AlphaMissense predicts likely benign (score 0.1707) — an in-silico prediction, not a clinical call.

CFAP61 p.Arg552Cys

c.1654C>T · rs370567248 · VCV2504103

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1707 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0824%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spermatogenic failure 84

Computational evidence

Protein change
AlphaMissense	0.1707	likely benign ⚠ discordant with ClinVar
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.10	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 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 304 kb · p 0.21 · regional, not allelic
Overall
CADD	25.5	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 0.0824% East Asian · 37/44,900 alleles

Filtering AF 0.0614% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00725% 117/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.11%	906
East Asiangrpmax	0.0824%	1,214
African / African-American	0.00801%	12,482
South Asian	0.0011%	91,082
European (non-Finnish)	0.000339%	295,006

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CFAP61
Protein: p.Arg552Cys
Coding: c.1654C>T
MANE Select: NM_015585
dbSNP: rs370567248
Type: single nucleotide variant
Location: chr20:20196633 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.86 · 1 PDB
Residue 552: a UniProt-annotated variant site (in spgf84; pathogenic; no protein detected in patient sperm); a UniProt-annotated variant site (in spgf84; uncertain significance)

Full CFAP61 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 84 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: situs inversus

Similar variants

CFAP61 c.3125-1G>C Likely pathogenic ★ same condition
CFAP61 p.Arg283Ter Pathogenic ★ same condition
CFAP61 p.Val755Ala Likely pathogenic ★ ⚠ same condition
CFAP61 c.143+5G>A Pathogenic same condition
CFAP61 c.144-2A>G Pathogenic same condition
CFAP61 p.Asp971Asn Pathogenic ⚠ same condition
CFAP61 p.Gly556Arg Pathogenic same condition
CFAP61 p.Ile151fs 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/cfap61-p-arg552cys (accessed [today's date]).

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