Is CCIN p.Pro565Ser (c.1693C>T) pathogenic?

CCIN p.Pro565Ser (c.1693C>T) is classified Uncertain significance in CCIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0178%, eas).

How common is CCIN p.Pro565Ser (c.1693C>T) in the general population?

CCIN p.Pro565Ser (c.1693C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about CCIN p.Pro565Ser (c.1693C>T)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

CCIN p.Pro565Ser

c.1693C>T · rs766649225 · VCV2588487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.12	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 0.6	GERP -0.3, phastCons 0.091
Regional constraint	o/e 0.82	unconstrained · MANE · 1,763 bp · p 7.5e-07 · regional, not allelic
Overall
CADD	9.098	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 0.0178% East Asian · 8/44,908 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00062% 10/1,614,068 alleles · ultra-rare exomes 9/1,461,816 · genomes 1/152,252 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,613
Admixed American	0.00333%	29,994

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: CCIN
Protein: p.Pro565Ser
Coding: c.1693C>T
MANE Select: NM_005893
dbSNP: rs766649225
Type: single nucleotide variant
Location: chr9:36171195 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 90.53
Residue 565: a UniProt-annotated variant site (in spgf91; pathogenic; in spermatozoa, undetectable in the postacrosomal region, suggesting that it could be degraded or shed during spermiogenesis; when tested in knockin mice, which also carry variant w-432, a setting similar to that of the original patient with this phenotype, animals develop normally, however, males are infertile and their spermatozoa show a substantial decrease in motility; spermatozoa from homozygous male mice exhibit several abnormalities, including abnormal head shaping, with an increase in their length and width, apical defect of the acrosome and nuclear lacunae devoid of chromatin; at the flagellum, mutant spermatozoa display mitochondrial sheath misassembly and coiling tail around the nucleus)

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

Similar variants

CCIN p.Arg485Trp Benign/Likely benign ★★ same type
CCIN p.Ala197Val Uncertain significance ★ ⚠ same type
CCIN p.Ala200Glu Uncertain significance ★ ⚠ same type
CCIN p.Ala200Thr Uncertain significance ★ ⚠ same type
CCIN p.Ala299Val Uncertain significance ★ ⚠ same type
CCIN p.Ala417Thr Uncertain significance ★ ⚠ same type
CCIN p.Ala536Ser Uncertain significance ★ ⚠ same type
CCIN p.Arg106Leu Uncertain significance ★ 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/ccin-p-pro565ser (accessed [today's date]).

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