Is CCDC77 p.Leu80Pro (c.239T>C) pathogenic?

CCDC77 p.Leu80Pro (c.239T>C) is classified Uncertain significance in CCDC77 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely pathogenic (0.9205); Very rare (popmax 0.00017%, nfe).

How common is CCDC77 p.Leu80Pro (c.239T>C) in the general population?

CCDC77 p.Leu80Pro (c.239T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CCDC77 p.Leu80Pro (c.239T>C)?

AlphaMissense predicts likely pathogenic (score 0.9205) — an in-silico prediction, not a clinical call.

CCDC77 p.Leu80Pro

c.239T>C · VCV3828792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9205	likely pathogenic · top 1% in CCDC77
REVEL	0.445	indeterminate
SaProt	LLR -15.00	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 33 kb · p 0.78 · regional, not allelic
Overall
CADD	26.2	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 0.00017% European (non-Finnish) · 2/1,179,918 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,780 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: CCDC77
Protein: p.Leu80Pro
Coding: c.239T>C
MANE Select: NM_032358
Type: single nucleotide variant
Location: chr12:411947 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.42

Full CCDC77 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC77 p.Ala157Pro Uncertain significance ★ ⚠ same type
CCDC77 p.Ala194Gly Uncertain significance ★ ⚠ same type
CCDC77 p.Ala445Pro Uncertain significance ★ ⚠ same type
CCDC77 p.Arg134Leu Uncertain significance ★ ⚠ same type
CCDC77 p.Arg216Gly Uncertain significance ★ ⚠ same type
CCDC77 p.Arg251Gln Uncertain significance ★ ⚠ same type
CCDC77 p.Arg251Leu Uncertain significance ★ ⚠ same type
CCDC77 p.Arg251Trp 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/ccdc77-p-leu80pro (accessed [today's date]).

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