Is CCDC136 p.Pro1069Ala (c.3205C>G) pathogenic?

CCDC136 p.Pro1069Ala (c.3205C>G) is classified Uncertain significance in CCDC136 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0776); Very rare (popmax 0.000258%, nfe).

How common is CCDC136 p.Pro1069Ala (c.3205C>G) in the general population?

CCDC136 p.Pro1069Ala (c.3205C>G) is very rare (popmax 0.000258%, nfe) (gnomAD).

What do computational predictors say about CCDC136 p.Pro1069Ala (c.3205C>G)?

AlphaMissense predicts likely benign (score 0.0776) — an in-silico prediction, not a clinical call.

CCDC136 p.Pro1069Ala

c.3205C>G · VCV4649020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000258%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0776	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.70	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 0.17
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 3e-06 · regional, not allelic
Overall
CADD	8.919	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 0.000258% European (non-Finnish) · 3/1,161,964 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00019% 3/1,577,006 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: CCDC136
Protein: p.Pro1069Ala
Coding: c.3205C>G
MANE Select: NM_022742
Type: single nucleotide variant
Location: chr7:128815773 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.24
Residue 1069: the 'disordered' region

Full CCDC136 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC136 p.Ala687= Benign ★★ same type
CCDC136 p.Asp218His Benign ★★ ⚠ same type
CCDC136 p.Glu1087= Benign ★★ same type
CCDC136 p.Glu1097Gly Likely benign ★★ ⚠ same type
CCDC136 p.Gly221= Benign ★★ same type
CCDC136 p.Gly980Arg Benign ★★ same type
CCDC136 p.Leu616= Benign ★★ same type
CCDC136 p.Val432Ile Benign ★★ 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/ccdc136-p-pro1069ala (accessed [today's date]).

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