Is CCIN p.Leu77Pro (c.230T>C) pathogenic?

CCIN p.Leu77Pro (c.230T>C) is classified Pathogenic in CCIN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely pathogenic (0.9408); Very rare (popmax 8.47e-05%, nfe); Associated with spermatogenic failure 91.

What condition is associated with CCIN p.Leu77Pro (c.230T>C)?

CCIN p.Leu77Pro (c.230T>C) is associated with spermatogenic failure 91 (ClinVar).

How common is CCIN p.Leu77Pro (c.230T>C) in the general population?

CCIN p.Leu77Pro (c.230T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CCIN p.Leu77Pro (c.230T>C)?

AlphaMissense predicts likely pathogenic (score 0.9408) — an in-silico prediction, not a clinical call.

CCIN p.Leu77Pro

c.230T>C · rs1228645269 · VCV3236749

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spermatogenic failure 91

Computational evidence

Protein change
AlphaMissense	0.9408	likely pathogenic ✓ concordant with ClinVar · top 9% in CCIN
REVEL	0.649	pathogenic-leaning
SaProt	LLR -13.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,763 bp · p 7.5e-07 · regional, not allelic
Overall
CADD	24.7	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 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.84e-05% 1/1,461,878 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.Leu77Pro
Coding: c.230T>C
MANE Select: NM_005893
dbSNP: rs1228645269
Type: single nucleotide variant
Location: chr9:36169732 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 90.53
Residue 77: the btb domain; a UniProt-annotated variant site (in spgf91; uncertain significance; strongly reduced expression at the calyx of the sperm head)

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

Disease context

spermatogenic failure 91 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCIN p.Arg432Trp Pathogenic same condition
CCIN p.Cys447Ter Pathogenic same condition
CCIN p.Gly285Ser Pathogenic same condition
CCIN p.His42Leu Pathogenic same condition
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

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-leu77pro (accessed [today's date]).

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