Is CCIN p.Cys576Arg (c.1726T>C) pathogenic?

CCIN p.Cys576Arg (c.1726T>C) is classified Uncertain significance in CCIN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely pathogenic (0.9709); Very rare (popmax 0.00223%, eas).

How common is CCIN p.Cys576Arg (c.1726T>C) in the general population?

CCIN p.Cys576Arg (c.1726T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCIN p.Cys576Arg (c.1726T>C)?

AlphaMissense predicts likely pathogenic (score 0.9709) — an in-silico prediction, not a clinical call.

CCIN p.Cys576Arg

c.1726T>C · VCV3487227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9709	likely pathogenic · top 5% in CCIN
REVEL	0.519	indeterminate
SaProt	LLR -14.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,763 bp · p 7.5e-07 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,890 alleles

Overall 0.000656% 1/152,368 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: CCIN
Protein: p.Cys576Arg
Coding: c.1726T>C
MANE Select: NM_005893
Type: single nucleotide variant
Location: chr9:36171228 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 90.53
Residue 576: 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-cys576arg (accessed [today's date]).

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